4-185019751-C-G

Variant names:

• chr4-185019751-C-G
• NM_001300781.2:c.137C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001300781.2(HELT):​c.137C>G​(p.Ser46Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HELT NM_001300781.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84

Genes affected

HELT (HGNC:33783): (helt bHLH transcription factor) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anterior/posterior pattern specification; regulation of neurogenesis; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including nervous system development; regulation of transcription by RNA polymerase II; and suckling behavior. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELT	NM_001300781.2	c.137C>G	p.Ser46Cys	missense_variant	Exon 3 of 4	ENST00000515777.6	NP_001287710.1
HELT	NM_001300782.2	c.137C>G	p.Ser46Cys	missense_variant	Exon 3 of 4		NP_001287711.1
HELT	XM_017008186.2	c.305C>G	p.Ser102Cys	missense_variant	Exon 3 of 4		XP_016863675.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELT	ENST00000515777.6	c.137C>G	p.Ser46Cys	missense_variant	Exon 3 of 4	1	NM_001300781.2	ENSP00000426033.1
HELT	ENST00000338875.5	c.392C>G	p.Ser131Cys	missense_variant	Exon 3 of 4	1		ENSP00000343464.4
HELT	ENST00000505610.5	c.137C>G	p.Ser46Cys	missense_variant	Exon 3 of 4	1		ENSP00000422140.1
HELT	ENST00000513599.1	n.480C>G		non_coding_transcript_exon_variant	Exon 2 of 3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461086 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.392C>G (p.S131C) alteration is located in exon 3 (coding exon 3) of the HELT gene. This alteration results from a C to G substitution at nucleotide position 392, causing the serine (S) at amino acid position 131 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Vest4		0.41
MutPred		0.78		.;.;Loss of disorder (P = 0.0174);
MVP		0.90
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.75
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-185940905;