1-34794607-C-T

Position:

chr1-34794607-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002060.3(GJA4):c.394C>T(p.Arg132Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00962 in 1,605,510 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 75 hom. )

Consequence

GJA4
NM_002060.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.75

Variant links:

Genes affected

GJA4 (HGNC:4278): (gap junction protein alpha 4) This gene encodes a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene have been associated with atherosclerosis and a higher risk of myocardial infarction. [provided by RefSeq, Jul 2008]

GJA4 links:

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007856071).

BP6

Variant 1-34794607-C-T is Benign according to our data. Variant chr1-34794607-C-T is described in ClinVar as [Benign]. Clinvar id is 789257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00981 (14251/1453264) while in subpopulation MID AF= 0.02 (115/5764). AF 95% confidence interval is 0.017. There are 75 homozygotes in gnomad4_exome. There are 7251 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA4	NM_002060.3 linkuse as main transcript	c.394C>T	p.Arg132Cys	missense_variant	2/2	ENST00000342280.5	NP_002051.2	P35212
GJA4	XM_005270750.3 linkuse as main transcript	c.394C>T	p.Arg132Cys	missense_variant	2/2		XP_005270807.1	P35212
GJA4	XM_017001043.3 linkuse as main transcript	c.394C>T	p.Arg132Cys	missense_variant	2/2		XP_016856532.1	P35212

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GJA4	ENST00000342280.5 linkuse as main transcript	c.394C>T	p.Arg132Cys	missense_variant	2/2	1	NM_002060.3	ENSP00000343676.4	P35212
SMIM12	ENST00000426886.1 linkuse as main transcript	n.207+61164G>A		intron_variant		1		ENSP00000429902.1	E5RH51
GJA4	ENST00000450137.1 linkuse as main transcript	c.394C>T	p.Arg132Cys	missense_variant	2/2	2		ENSP00000409186.1	Q5JW71

Frequencies

GnomAD3 genomes

AF:

0.00787

AC:

1197

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.00819

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00929

AC:

2268

AN:

244020

Hom.:

AF XY:

0.00987

AC XY:

1308

AN XY:

132496

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.00499

Gnomad ASJ exome

AF:

0.0196

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0136

Gnomad FIN exome

AF:

0.00934

Gnomad NFE exome

AF:

0.0111

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.00981

AC:

14251

AN:

1453264

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

7251

AN XY:

723290

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00532

Gnomad4 ASJ exome

AF:

0.0206

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0140

Gnomad4 FIN exome

AF:

0.00980

Gnomad4 NFE exome

AF:

0.00994

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.00787

AC:

1198

AN:

152246

Hom.:

Cov.:

AF XY:

0.00769

AC XY:

572

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.00758

Gnomad4 ASJ

AF:

0.0248

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0143

Gnomad4 FIN

AF:

0.00819

Gnomad4 NFE

AF:

0.0108

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.0113

Hom.:

Bravo

AF:

0.00699

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00965

AC:

ExAC

AF:

0.00941

AC:

1142

Asia WGS

AF:

0.00318

AC:

AN:

3476

EpiCase

AF:

0.0119

EpiControl

AF:

0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	GJA4: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.

Eigen

Benign

0.060

Eigen_PC

Benign

0.072

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0079

T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.41

Sift

Benign

0.046

D;D

Sift4G

Uncertain

0.035

D;D

Polyphen

0.95

P;P

Vest4

0.23

MVP

0.97

MPC

0.82

ClinPred

0.020

GERP RS

4.1

Varity_R

0.16

gMVP

0.58

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