Menu
GeneBe

1-34761392-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_153212.3(GJB4):c.138T>C(p.Asp46=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000809 in 1,613,584 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0045 ( 7 hom., cov: 33)
Exomes 𝑓: 0.00043 ( 6 hom. )

Consequence

GJB4
NM_153212.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -4.23
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 -15 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=-0.75).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-34761392-T-C is Benign according to our data. Variant chr1-34761392-T-C is described in ClinVar as [Benign]. Clinvar id is 780229.Status of the report is criteria_provided_single_submitter, 1 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=-4.23 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00447 (679/151866) while in subpopulation AFR AF= 0.0156 (646/41320). AF 95% confidence interval is 0.0146. There are 7 homozygotes in gnomad4. There are 332 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 683 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GJB4NM_153212.3 linkuse as main transcriptc.138T>C p.Asp46= synonymous_variant 2/2 ENST00000339480.3
GJB4XM_011540679.3 linkuse as main transcriptc.138T>C p.Asp46= synonymous_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GJB4ENST00000339480.3 linkuse as main transcriptc.138T>C p.Asp46= synonymous_variant 2/22 NM_153212.3 P1
SMIM12ENST00000426886.1 linkuse as main transcriptc.208-42983A>G intron_variant, NMD_transcript_variant 1
ENST00000542839.1 linkuse as main transcript downstream_gene_variant 5

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00450
AC:
683
AN:
151746
Hom.:
7
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0158
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00170
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00336
GnomAD3 exomes
AF:
0.00108
AC:
272
AN:
251280
Hom.:
4
AF XY:
0.000854
AC XY:
116
AN XY:
135824
show subpopulations
Gnomad AFR exome
AF:
0.0153
Gnomad AMR exome
AF:
0.000492
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000978
GnomAD4 exome
AF:
0.000428
AC:
626
AN:
1461718
Hom.:
6
Cov.:
31
AF XY:
0.000370
AC XY:
269
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.0162
Gnomad4 AMR exome
AF:
0.000559
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.000811
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00447
AC:
679
AN:
151866
Hom.:
7
Cov.:
33
AF XY:
0.00447
AC XY:
332
AN XY:
74232
show subpopulations
Gnomad4 AFR
AF:
0.0156
Gnomad4 AMR
AF:
0.00170
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00332
Alfa
AF:
0.00216
Hom.:
0
Bravo
AF:
0.00510
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeOct 11, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
Cadd
Benign
0.016
Dann
Benign
0.56

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: rs151304203; hg19: chr1-35226993; API