1-34761440-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153212.3(GJB4):c.186C>T(p.Asn62=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,614,136 control chromosomes in the GnomAD database, including 583 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (295 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (288 hom.)
• Consequence: GJB4 NM_153212.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.78

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]

(HGNC:):

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

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-34761440-C-T is Benign according to our data. Variant chr1-34761440-C-T is described in ClinVar as [Benign]. Clinvar id is 1250735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB4	NM_153212.3	c.186C>T	p.Asn62=	synonymous_variant	2/2	ENST00000339480.3
GJB4	XM_011540679.3	c.186C>T	p.Asn62=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB4	ENST00000339480.3	c.186C>T	p.Asn62=	synonymous_variant	2/2	2	NM_153212.3	P1
	ENST00000542839.1	n.546G>A		non_coding_transcript_exon_variant	2/2	5
SMIM12	ENST00000426886.1	c.208-43031G>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 5096 AN: 152212 Hom.: 295 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.00904 AC: 2269 AN: 250986 Hom.: 114 AF XY: 0.00656 AC XY: 890 AN XY: 135668

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.00709

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000625

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00376 AC: 5497 AN: 1461806 Hom.: 288 Cov.: 31 AF XY: 0.00328 AC XY: 2385 AN XY: 727188

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.00814

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.00839

GnomAD4 genome AF: 0.0335 AC: 5106 AN: 152330 Hom.: 295 Cov.: 33 AF XY: 0.0327 AC XY: 2437 AN XY: 74494

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0139 Hom.: 50

Bravo AF: 0.0387

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000593

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	Nov 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	1.5
Dann	Benign	0.88

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: rs76188300; hg19: chr1-35227041; COSMIC: COSV58355773; COSMIC: COSV58355773;