1-34795168-C-T

Variant names:

• chr1-34795168-C-T
• rs1764391
• NM_002060.3:c.955C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002060.3(GJA4):​c.955C>T​(p.Pro319Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,611,582 control chromosomes in the GnomAD database, including 78,464 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (11321 hom., cov: 31)
  • Exomes 𝑓: 0.30 (67143 hom.)
• Consequence: GJA4 NM_002060.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.296
• Publications: 99 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5687552E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

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.955C>T	p.Pro319Ser	missense	Exon 2 of 2	NP_002051.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA4	ENST00000342280.5	TSL:1 MANE Select	c.955C>T	p.Pro319Ser	missense	Exon 2 of 2	ENSP00000343676.4
	SMIM12	ENST00000426886.1	TSL:1	n.207+60603G>A		intron	N/A	ENSP00000429902.1
	GJA4	ENST00000868038.1		c.955C>T	p.Pro319Ser	missense	Exon 2 of 2	ENSP00000538097.1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55742 AN: 151704 Hom.: 11307 Cov.: 31

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.338

GnomAD2 exomes AF: 0.303 AC: 75790 AN: 249984 AF XY: 0.298

Gnomad AFR exome AF: 0.539

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.292

Gnomad EAS exome AF: 0.172

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.297 AC: 433317 AN: 1459762 Hom.: 67143 Cov.: 34 AF XY: 0.295 AC XY: 214362 AN XY: 726284

African (AFR) AF: 0.541 AC: 18115 AN: 33454

American (AMR) AF: 0.244 AC: 10896 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 7567 AN: 26094

East Asian (EAS) AF: 0.181 AC: 7187 AN: 39688

South Asian (SAS) AF: 0.223 AC: 19261 AN: 86186

European-Finnish (FIN) AF: 0.431 AC: 22923 AN: 53230

Middle Eastern (MID) AF: 0.321 AC: 1852 AN: 5768

European-Non Finnish (NFE) AF: 0.295 AC: 327400 AN: 1110348

Other (OTH) AF: 0.300 AC: 18116 AN: 60316

GnomAD4 genome AF: 0.367 AC: 55785 AN: 151820 Hom.: 11321 Cov.: 31 AF XY: 0.367 AC XY: 27189 AN XY: 74130

African (AFR) AF: 0.540 AC: 22344 AN: 41408

American (AMR) AF: 0.274 AC: 4191 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1030 AN: 3470

East Asian (EAS) AF: 0.177 AC: 911 AN: 5136

South Asian (SAS) AF: 0.217 AC: 1041 AN: 4804

European-Finnish (FIN) AF: 0.430 AC: 4528 AN: 10532

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20756 AN: 67892

Other (OTH) AF: 0.335 AC: 704 AN: 2104

Alfa AF: 0.317 Hom.: 24181

Bravo AF: 0.362

TwinsUK AF: 0.289 AC: 1071

ALSPAC AF: 0.285 AC: 1100

ESP6500AA AF: 0.525 AC: 2315

ESP6500EA AF: 0.303 AC: 2603

ExAC AF: 0.310 AC: 37594

Asia WGS AF: 0.226 AC: 786 AN: 3478

EpiCase AF: 0.307

EpiControl AF: 0.303

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.68
DANN	Benign	0.54
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.000016	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.58	N
PhyloP100		-0.30
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.24
Sift	Benign	0.80	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.021
MPC		0.49
ClinPred		0.00026	T
GERP RS		0.013
Varity_R		0.028
gMVP		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1764391; hg19: chr1-35260769; COSMIC: COSV60724736; COSMIC: COSV60724736;