1-34761406-TTGTC-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00900

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• 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 GnomAd at 4483 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB4	NM_153212.3	c.155_158del	p.Val52AlafsTer55	frameshift_variant	2/2	ENST00000339480.3
GJB4	XM_011540679.3	c.155_158del	p.Val52AlafsTer55	frameshift_variant	2/2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4483 AN: 147424 Hom.: 95 Cov.: 32

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

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

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.: 94 Cov.: 32 AF XY: 0.0300 AC XY: 2168 AN XY: 72170

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.: 25

Bravo AF: 0.0257

Asia WGS AF: 0.00724 AC: 25 AN: 3468

EpiCase AF: 0.0400

EpiControl AF: 0.0378

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs146812843; hg19: chr1-35227007;