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GeneBe

1-34761437-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_153212.3(GJB4):c.183C>A(p.Pro61=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,614,148 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 66 hom., cov: 33)
Exomes 𝑓: 0.0016 ( 61 hom. )

Consequence

GJB4
NM_153212.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.380
Variant links:
Genes affected
GJB4 (HGNC:4286): (gap junction protein beta 4) This gene encodes a transmembrane connexin protein that is a component of gap junctions. Mutations in this gene have been associated with erythrokeratodermia variabilis, progressive symmetric erythrokeratoderma and hearing impairment. [provided by RefSeq, Dec 2009]
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 -19 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.41).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-34761437-C-A is Benign according to our data. Variant chr1-34761437-C-A is described in ClinVar as [Benign]. Clinvar id is 791789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.38 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GJB4NM_153212.3 linkuse as main transcriptc.183C>A p.Pro61= synonymous_variant 2/2 ENST00000339480.3
GJB4XM_011540679.3 linkuse as main transcriptc.183C>A p.Pro61= synonymous_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GJB4ENST00000339480.3 linkuse as main transcriptc.183C>A p.Pro61= synonymous_variant 2/22 NM_153212.3 P1
ENST00000542839.1 linkuse as main transcriptn.549G>T non_coding_transcript_exon_variant 2/25
SMIM12ENST00000426886.1 linkuse as main transcriptc.208-43028G>T intron_variant, NMD_transcript_variant 1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0152
AC:
2321
AN:
152210
Hom.:
66
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0533
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00549
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00860
GnomAD3 exomes
AF:
0.00399
AC:
1001
AN:
251024
Hom.:
33
AF XY:
0.00279
AC XY:
378
AN XY:
135694
show subpopulations
Gnomad AFR exome
AF:
0.0549
Gnomad AMR exome
AF:
0.00258
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000529
Gnomad OTH exome
AF:
0.00180
GnomAD4 exome
AF:
0.00158
AC:
2305
AN:
1461820
Hom.:
61
Cov.:
31
AF XY:
0.00134
AC XY:
971
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.0568
Gnomad4 AMR exome
AF:
0.00277
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000414
Gnomad4 OTH exome
AF:
0.00343
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0153
AC:
2325
AN:
152328
Hom.:
66
Cov.:
33
AF XY:
0.0149
AC XY:
1108
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0533
Gnomad4 AMR
AF:
0.00549
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00851
Alfa
AF:
0.00757
Hom.:
9
Bravo
AF:
0.0174
Asia WGS
AF:
0.00260
AC:
9
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 18, 2024- -
GJB4-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 24, 2020This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.41
Cadd
Benign
15
Dann
Benign
0.91

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: rs75121921; hg19: chr1-35227038; API