NM_002060.3:c.394C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

12 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 7251 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002060.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA4	NM_002060.3	MANE Select	c.394C>T	p.Arg132Cys	missense	Exon 2 of 2	NP_002051.2	P35212

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GJA4	ENST00000342280.5	TSL:1 MANE Select	c.394C>T	p.Arg132Cys	missense	Exon 2 of 2	ENSP00000343676.4	P35212
SMIM12	ENST00000426886.1	TSL:1	n.207+61164G>A		intron	N/A	ENSP00000429902.1	E5RH51
GJA4	ENST00000868038.1		c.394C>T	p.Arg132Cys	missense	Exon 2 of 2	ENSP00000538097.1

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

GnomAD2 exomes

AF:

0.00929

AC:

2268

AN:

244020

AF XY:

0.00987

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 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

African (AFR)

AF:

0.00128

AC:

AN:

33476

American (AMR)

AF:

0.00532

AC:

238

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0206

AC:

537

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0140

AC:

1207

AN:

86238

European-Finnish (FIN)

AF:

0.00980

AC:

442

AN:

45094

Middle Eastern (MID)

AF:

0.0200

AC:

115

AN:

5764

European-Non Finnish (NFE)

AF:

0.00994

AC:

11048

AN:

1111854

Other (OTH)

AF:

0.0103

AC:

620

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

874

1748

2622

3496

4370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

404

808

1212

1616

2020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00787

AC:

1198

AN:

152246

Hom.:

Cov.:

AF XY:

0.00769

AC XY:

572

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

41560

American (AMR)

AF:

0.00758

AC:

116

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.0143

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00819

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0108

AC:

735

AN:

68006

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0101

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Benign

0.060

Eigen_PC

Benign

0.072

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0079

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.4

PhyloP100

3.7

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.41

Sift

Benign

0.046

Sift4G

Uncertain

0.035

Polyphen

0.95

Vest4

0.23

MVP

0.97

MPC

0.82

ClinPred

0.020

GERP RS

4.1

Varity_R

0.16

gMVP

0.58

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over