4-185019670-C-G

Variant names:

• chr4-185019670-C-G
• rs758698183
• ENST00000338875.5:c.311C>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000338875.5(HELT):​c.311C>G​(p.Ser104Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HELT ENST00000338875.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.366

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060925514).
• BP6: Variant 4-185019670-C-G is Benign according to our data. Variant chr4-185019670-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3524939.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELT	NM_001300781.2	c.133-77C>G		intron_variant	Intron 2 of 3	ENST00000515777.6	NP_001287710.1
HELT	NM_001300782.2	c.133-77C>G		intron_variant	Intron 2 of 3		NP_001287711.1
HELT	XM_017008186.2	c.301-77C>G		intron_variant	Intron 2 of 3		XP_016863675.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELT	ENST00000338875.5	c.311C>G	p.Ser104Trp	missense_variant	Exon 3 of 4	1		ENSP00000343464.4
HELT	ENST00000515777.6	c.133-77C>G		intron_variant	Intron 2 of 3	1	NM_001300781.2	ENSP00000426033.1
HELT	ENST00000505610.5	c.133-77C>G		intron_variant	Intron 2 of 3	1		ENSP00000422140.1
HELT	ENST00000513599.1	n.399C>G		non_coding_transcript_exon_variant	Exon 2 of 3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458014 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 21, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.1
DANN	Benign	0.63
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.023
Sift	Benign	0.10	T
Sift4G	Uncertain	0.051	T
Vest4		0.18
MutPred		0.46		Loss of disorder (P = 0);
MVP		0.085
MPC		0.63
ClinPred		0.075	T
GERP RS		-4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs758698183; hg19: chr4-185940824;