chr1-34757455-G-T

Variant names:

• chr1-34757455-G-T
• rs143433567
• NM_005268.4:c.125G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005268.4(GJB5):​c.125G>T​(p.Arg42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R42C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJB5 NM_005268.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76

Genes affected

GJB5 (HGNC:4287): (gap junction protein beta 5) This gene encodes a member of the beta-type (group I) connexin family. The encoded protein is a gap junction protein involved in intercellular communication related to epidermal differentiation and environmental sensing. This gene has been linked to non-small cell lung cancer. [provided by RefSeq, Nov 2012]

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB5	NM_005268.4	c.125G>T	p.Arg42Leu	missense_variant	Exon 2 of 2	ENST00000338513.1	NP_005259.1
GJB5	XM_005270751.4	c.125G>T	p.Arg42Leu	missense_variant	Exon 2 of 2		XP_005270808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB5	ENST00000338513.1	c.125G>T	p.Arg42Leu	missense_variant	Exon 2 of 2	1	NM_005268.4	ENSP00000340811.1
SMIM12	ENST00000426886.1	n.208-39046C>A		intron_variant	Intron 2 of 4	1		ENSP00000429902.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.42
Sift	Benign	0.11	T
Sift4G	Benign	0.13	T
Polyphen		0.69	P
Vest4		0.51
MutPred		0.58		Gain of catalytic residue at R42 (P = 0.0461);
MVP		0.87
MPC		0.41
ClinPred		0.99	D
GERP RS		0.13
Varity_R		0.20
gMVP		0.71

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: rs143433567; hg19: chr1-35223056;