NHLH1

Chr 1

nescient helix-loop-helix 1

Also known as: HEN1, NSCL, NSCL1, bHLHa35

NCBI Gene: 4807 ENSG00000171786 UniProt: Q02575 OMIM: 162360

The helix-loop-helix (HLH) proteins are a family of putative transcription factors, some of which have been shown to play an important role in growth and development of a wide variety of tissues and species. Four members of this family have been clearly implicated in tumorigenesis via their involvement in chromosomal translocations in lymphoid tumors: MYC (MIM 190080), LYL1 (MIM 151440), E2A (MIM 147141), and SCL (MIM 187040).[supplied by OMIM, Nov 2002]

OMIM Research

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.31

Clinical Summary— NHLH1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

15 VUS of 17 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.31LOEUF

pLI 0.257

Z-score 1.23

OE 0.29 (0.10–1.31)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.04Z-score

OE missense 0.71 (0.58–0.86)

71 obs / 100.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.10–1.31)

0≤0.351.4

Missense OE?0.71 (0.58–0.86)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 1 / 3.5Missense obs/exp: 71 / 100.3Syn Z: 0.09

This gene — mechanism propensity

0.6552th %ile

GOF

0.5268th %ile

LOF

0.49top 25%

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

17 submitted variants in ClinVar

ClinVar

Classification Summary

VUS15

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	15	15
Likely Benign	0	0
Benign	0	0
Total	15	15

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap NHLH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →