rs139849901

chr1-34761404-CT-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_153212.3(GJB4):c.153del(p.Phe51LeufsTer57) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,613,820 control chromosomes in the GnomAD database, including 148 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (77 hom.)
• Consequence: GJB4 NM_153212.3 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.97

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 1-34761404-CT-C is Benign according to our data. Variant chr1-34761404-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 195421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB4	NM_153212.3	c.153del	p.Phe51LeufsTer57	frameshift_variant	2/2	ENST00000339480.3
GJB4	XM_011540679.3	c.153del	p.Phe51LeufsTer57	frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB4	ENST00000339480.3	c.153del	p.Phe51LeufsTer57	frameshift_variant	2/2	2	NM_153212.3	P1
SMIM12	ENST00000426886.1	c.208-42996del		intron_variant, NMD_transcript_variant		1
	ENST00000542839.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2464 AN: 151838 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00408 AC: 1022 AN: 250726 Hom.: 27 AF XY: 0.00299 AC XY: 405 AN XY: 135526

Gnomad AFR exome AF: 0.0560

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00169 AC: 2471 AN: 1461862 Hom.: 77 Cov.: 31 AF XY: 0.00145 AC XY: 1057 AN XY: 727228

Gnomad4 AFR exome AF: 0.0591

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.0162 AC: 2468 AN: 151958 Hom.: 71 Cov.: 32 AF XY: 0.0161 AC XY: 1197 AN XY: 74284

Gnomad4 AFR AF: 0.0568

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00764 Hom.: 6

Bravo AF: 0.0184

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 30, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 24, 2023

- -

Erythrokeratodermia variabilis et progressiva 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

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: rs139849901; hg19: chr1-35227005;