rs74315320

chr1-34785183-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_024009.3(GJB3):c.421A>G(p.Ile141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I141N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJB3 NM_024009.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.16

Genes affected

GJB3 (HGNC:4285): (gap junction protein beta 3) This gene is 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 can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein. [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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a transmembrane_region Helical (size 22) in uniprot entity CXB3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_024009.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-34785183-A-G is Pathogenic according to our data. Variant chr1-34785183-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6488.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-34785183-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB3	NM_024009.3	c.421A>G	p.Ile141Val	missense_variant	2/2	ENST00000373366.3
GJB3	NM_001005752.2	c.421A>G	p.Ile141Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB3	ENST00000373366.3	c.421A>G	p.Ile141Val	missense_variant	2/2	1	NM_024009.3	P1
GJB3	ENST00000373362.3	c.421A>G	p.Ile141Val	missense_variant	2/2	1		P1
SMIM12	ENST00000426886.1	c.208-66774T>C		intron_variant, NMD_transcript_variant		1
	ENST00000542839.1	n.110+2805T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hearing loss, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	0.35	N;N
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.090	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.37	T;T
Sift4G	Benign	0.63	T;T
Polyphen		0.0010	B;B
Vest4		0.70
MutPred		0.60		Loss of catalytic residue at L146 (P = 0.0539);Loss of catalytic residue at L146 (P = 0.0539);
MVP		0.68
MPC		0.062
ClinPred		0.19	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.68

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: rs74315320; hg19: chr1-35250784;