chr1-34785261-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4_StrongBP6BS1BS2_Supporting

The NM_024009.3(GJB3):​c.499G>A​(p.Val167Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

GJB3
NM_024009.3 missense

Scores

5
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.30
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM1
In a chain Gap junction beta-3 protein (size 269) in uniprot entity CXB3_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_024009.3
BP4
Computational evidence support a benign effect (MetaRNN=0.021685094).
BP6
Variant 1-34785261-G-A is Benign according to our data. Variant chr1-34785261-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289016.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000855 (13/152118) while in subpopulation SAS AF= 0.00146 (7/4804). AF 95% confidence interval is 0.000684. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 13 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GJB3NM_024009.3 linkuse as main transcriptc.499G>A p.Val167Met missense_variant 2/2 ENST00000373366.3 NP_076872.1
GJB3NM_001005752.2 linkuse as main transcriptc.499G>A p.Val167Met missense_variant 2/2 NP_001005752.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GJB3ENST00000373366.3 linkuse as main transcriptc.499G>A p.Val167Met missense_variant 2/21 NM_024009.3 ENSP00000362464 P1
GJB3ENST00000373362.3 linkuse as main transcriptc.499G>A p.Val167Met missense_variant 2/21 ENSP00000362460 P1
SMIM12ENST00000426886.1 linkuse as main transcriptc.208-66852C>T intron_variant, NMD_transcript_variant 1 ENSP00000429902
ENST00000542839.1 linkuse as main transcriptn.110+2727C>T intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000855
AC:
13
AN:
152000
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00146
Gnomad FIN
AF:
0.0000946
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000239
AC:
60
AN:
251328
Hom.:
1
AF XY:
0.000339
AC XY:
46
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00173
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000156
AC:
228
AN:
1461634
Hom.:
1
Cov.:
33
AF XY:
0.000201
AC XY:
146
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00180
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000432
Gnomad4 OTH exome
AF:
0.000248
GnomAD4 genome
AF:
0.0000855
AC:
13
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00146
Gnomad4 FIN
AF:
0.0000946
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000381
Hom.:
0
Bravo
AF:
0.0000680
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000272
AC:
33
Asia WGS
AF:
0.000578
AC:
2
AN:
3476
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 08, 2023- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 11, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 04, 2016- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 25, 2020- -
Autosomal recessive nonsyndromic hearing loss 1A;C2675236:Autosomal dominant nonsyndromic hearing loss 2B;C4551486:Erythrokeratodermia variabilis et progressiva 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.52
D;D
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.37
N
LIST_S2
Benign
0.85
.;T
M_CAP
Uncertain
0.087
D
MetaRNN
Benign
0.022
T;T
MetaSVM
Uncertain
0.048
D
MutationAssessor
Uncertain
2.1
M;M
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.80
N;N
REVEL
Benign
0.25
Sift
Benign
0.27
T;T
Sift4G
Benign
0.18
T;T
Polyphen
0.44
B;B
Vest4
0.18
MVP
0.75
MPC
0.11
ClinPred
0.016
T
GERP RS
3.2
Varity_R
0.036
gMVP
0.66

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs376748531; hg19: chr1-35250862; API