rs80358207

Positions:

• chr1-34761663-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP3_Moderate PP5_Moderate

The NM_153212.3(GJB4):​c.409T>C​(p.Phe137Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. F137F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB4 NM_153212.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.31

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]

ENSG00000255811 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_153212.3 (GJB4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 5005
• PM1: In a transmembrane_region Helical (size 20) in uniprot entity CXB4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_153212.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 1-34761663-T-C is Pathogenic according to our data. Variant chr1-34761663-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5004.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-34761663-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB4	NM_153212.3	c.409T>C	p.Phe137Leu	missense_variant	2/2	ENST00000339480.3	NP_694944.1
GJB4	XM_011540679.3	c.409T>C	p.Phe137Leu	missense_variant	2/2		XP_011538981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB4	ENST00000339480.3	c.409T>C	p.Phe137Leu	missense_variant	2/2	2	NM_153212.3	ENSP00000345868.1
SMIM12	ENST00000426886.1	n.208-43254A>G		intron_variant		1		ENSP00000429902.1
ENSG00000255811	ENST00000542839.1	n.323A>G		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 30, 2023

Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11017804, 12648223, 148984) -

Erythrokeratodermia variabilis et progressiva 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.066
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.75
Sift	Benign	0.069	T
Sift4G	Benign	0.091	T
Polyphen		0.017	B
Vest4		0.72
MutPred		0.86		Loss of methylation at K138 (P = 0.0778);
MVP		0.98
MPC		0.10
ClinPred		0.83	D
GERP RS		4.6
Varity_R		0.51
gMVP		0.72

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: rs80358207; hg19: chr1-35227264;