1-34757455-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005268.4(GJB5):​c.125G>A​(p.Arg42His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,614,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: GJB5 NM_005268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20399243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB5	NM_005268.4	c.125G>A	p.Arg42His	missense_variant	Exon 2 of 2	ENST00000338513.1	NP_005259.1
GJB5	XM_005270751.4	c.125G>A	p.Arg42His	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>A	p.Arg42His	missense_variant	Exon 2 of 2	1	NM_005268.4	ENSP00000340811.1
SMIM12	ENST00000426886.1	n.208-39046C>T		intron_variant	Intron 2 of 4	1		ENSP00000429902.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251450 AF XY: 0.000250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000413

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000395 AC: 577 AN: 1461890 Hom.: 1 Cov.: 32 AF XY: 0.000344 AC XY: 250 AN XY: 727244

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000470 AC: 523 AN: 1112010

Other (OTH) AF: 0.000348 AC: 21 AN: 60394

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125G>A (p.R42H) alteration is located in exon 2 (coding exon 1) of the GJB5 gene. This alteration results from a G to A substitution at nucleotide position 125, causing the arginine (R) at amino acid position 42 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.41
Sift	Benign	0.29	T
Sift4G	Benign	0.29	T
Polyphen		0.034	B
Vest4		0.16
MVP		0.82
MPC		0.17
ClinPred		0.064	T
GERP RS		0.13
Varity_R		0.035
gMVP		0.51
Mutation Taster		=90/10	polymorphism

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: rs143433567; hg19: chr1-35223056;