Variant 3-125001931-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020733.2(HEG1):c.3438G>C(p.Arg1146Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HEG1
NM_020733.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.148

Variant links:

Genes affected

HEG1 (HGNC:29227): (heart development protein with EGF like domains 1) Predicted to enable calcium ion binding activity. Involved in several processes, including negative regulation of Rho protein signal transduction; negative regulation of Rho-dependent protein serine/threonine kinase activity; and negative regulation of membrane permeability. Located in cell-cell junction. [provided by Alliance of Genome Resources, Apr 2022]

HEG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056001395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEG1	NM_020733.2 link	c.3438G>C	p.Arg1146Ser	missense_variant	11/17	ENST00000311127.9	NP_065784.1	Q9ULI3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEG1	ENST00000311127.9 link	c.3438G>C	p.Arg1146Ser	missense_variant	11/17	5	NM_020733.2	ENSP00000311502.3		Q9ULI3-1
HEG1	ENST00000650592.2 link	c.3738G>C	p.Arg1246Ser	missense_variant	12/18			ENSP00000515478.1		A0A994J6K3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

The c.3438G>C (p.R1146S) alteration is located in exon 11 (coding exon 11) of the HEG1 gene. This alteration results from a G to C substitution at nucleotide position 3438, causing the arginine (R) at amino acid position 1146 to be replaced by a serine (S). 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

Benign

0.17

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Benign

9.8

DANN

Benign

0.92

DEOGEN2

Benign

0.047

T;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.44

N;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.81

N;N

REVEL

Benign

0.057

Sift

Benign

0.62

T;T

Sift4G

Benign

0.98

T;T

Polyphen

0.019

B;.

Vest4

0.15

MutPred

0.46

Gain of disorder (P = 0.0699);.;

MVP

0.67

MPC

0.12

ClinPred

0.27

GERP RS

2.7

Varity_R

0.14

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over