HNRNPDL

Chr 4AD

heterogeneous nuclear ribonucleoprotein D like

Also known as: HNRNP, HNRPDL, JKTBP, JKTBP2, LGMD1G, LGMDD3, laAUF1

NCBI Gene: 9987 ENSG00000152795 UniProt: O14979 OMIM: 607137

The protein binds RNA through two RRM domains and regulates pre-mRNA processing and mRNA metabolism in the nucleus. Mutations cause limb-girdle muscular dystrophy type 3 with autosomal dominant inheritance. The pathogenic mechanism involves disrupted RNA processing that leads to progressive muscle weakness and atrophy primarily affecting the shoulder and pelvic girdle muscles.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two RRM domains that bind to RNAs. Three alternatively spliced transcript variants have been described for this gene. One of the variants is probably not translated because the transcript is a candidate for nonsense-mediated mRNA decay. The protein isoforms encoded by this gene are similar to its family member HNRPD. [provided by RefSeq, May 2011]

OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.551 OMIM phenotype

Clinical Summary— HNRNPDL

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Gene-Disease Validity (ClinGen)

muscular dystrophy, limb-girdle, autosomal dominant · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 278 VUS of 504 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.078

Z-score 3.09

OE 0.28 (0.15–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.70Z-score

OE missense 0.86 (0.77–0.98)

182 obs / 210.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.28 (0.15–0.55)

0≤0.351.4

Missense OE?0.86 (0.77–0.98)

0≤0.61.4

Synonymous OE?1.62

0≤1.21.6

LoF obs/exp: 6 / 21.4Missense obs/exp: 182 / 210.6Syn Z: -4.33

This gene — mechanism propensity

0.7033th %ile

GOF

0.5269th %ile

LOF

0.4529th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

504 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic3

VUS278

Likely Benign184

Benign19

Conflicting10

Likely Pathogenic

278

VUS

184

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	3	0	0	3
VUS	14	251	10	3	278
Likely Benign	0	3	42	139	184
Benign	0	1	13	5	19
Conflicting	—				10
Total	14	258	65	147	494

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

40 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap HNRNPDL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →