Variant chr1-34761406-TTGTC-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_StrongBP6_Very_StrongBS1BS2

The NM_153212.3(GJB4):c.155_158del(p.Val52AlafsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0413 in 1,609,388 control chromosomes in the GnomAD database, including 1,553 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 94 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1459 hom. )

Consequence

GJB4
NM_153212.3 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: -0.00900

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]

GJB4 links:

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM12 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.

BP6

Variant 1-34761406-TTGTC-T is Benign according to our data. Variant chr1-34761406-TTGTC-T is described in ClinVar as [Benign]. Clinvar id is 1276227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0304 (4481/147534) while in subpopulation NFE AF= 0.0454 (3087/67988). AF 95% confidence interval is 0.0441. There are 94 homozygotes in gnomad4. There are 2168 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4481 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB4	NM_153212.3 linkuse as main transcript	c.155_158del	p.Val52AlafsTer55	frameshift_variant	2/2	ENST00000339480.3	NP_694944.1
GJB4	XM_011540679.3 linkuse as main transcript	c.155_158del	p.Val52AlafsTer55	frameshift_variant	2/2		XP_011538981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GJB4	ENST00000339480.3 linkuse as main transcript	c.155_158del	p.Val52AlafsTer55	frameshift_variant	2/2	2	NM_153212.3	ENSP00000345868	P1
SMIM12	ENST00000426886.1 linkuse as main transcript	c.208-43001_208-42998del		intron_variant, NMD_transcript_variant		1		ENSP00000429902
	ENST00000542839.1 linkuse as main transcript			downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0304

AC:

4483

AN:

147424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00897

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0179

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0217

Gnomad FIN

AF:

0.0536

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0454

Gnomad OTH

AF:

0.0250

GnomAD3 exomes

AF:

0.0327

AC:

8149

AN:

249250

Hom.:

171

AF XY:

0.0337

AC XY:

4553

AN XY:

135008

show subpopulations

Gnomad AFR exome

AF:

0.00842

Gnomad AMR exome

AF:

0.0148

Gnomad ASJ exome

AF:

0.0154

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0271

Gnomad FIN exome

AF:

0.0538

Gnomad NFE exome

AF:

0.0455

Gnomad OTH exome

AF:

0.0322

GnomAD4 exome

AF:

0.0423

AC:

61909

AN:

1461854

Hom.:

1459

AF XY:

0.0421

AC XY:

30628

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00657

Gnomad4 AMR exome

AF:

0.0161

Gnomad4 ASJ exome

AF:

0.0158

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0272

Gnomad4 FIN exome

AF:

0.0556

Gnomad4 NFE exome

AF:

0.0476

Gnomad4 OTH exome

AF:

0.0370

GnomAD4 genome

AF:

0.0304

AC:

4481

AN:

147534

Hom.:

Cov.:

AF XY:

0.0300

AC XY:

2168

AN XY:

72170

show subpopulations

Gnomad4 AFR

AF:

0.00894

Gnomad4 AMR

AF:

0.0179

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0216

Gnomad4 FIN

AF:

0.0536

Gnomad4 NFE

AF:

0.0454

Gnomad4 OTH

AF:

0.0248

Alfa

AF:

0.0349

Hom.:

Bravo

AF:

0.0257

Asia WGS

AF:

0.00724

AC:

AN:

3468

EpiCase

AF:

0.0400

EpiControl

AF:

0.0378

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over