rs80358207

Variant names:

• chr1-34761663-T-C
• rs80358207
• NM_153212.3:c.409T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 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 the same amino acid substitution has been previously reported as Pathogenic in 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
• Publications: 16 publications found

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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_153212.3 (GJB4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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 VariationId is 5004.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB4	NM_153212.3	c.409T>C	p.Phe137Leu	missense_variant	Exon 2 of 2	ENST00000339480.3	NP_694944.1
GJB4	XM_011540679.3	c.409T>C	p.Phe137Leu	missense_variant	Exon 2 of 2		XP_011538981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB4	ENST00000339480.3	c.409T>C	p.Phe137Leu	missense_variant	Exon 2 of 2	2	NM_153212.3	ENSP00000345868.1
SMIM12	ENST00000426886.1	n.208-43254A>G		intron_variant	Intron 2 of 4	1		ENSP00000429902.1
ENSG00000255811	ENST00000542839.1	n.323A>G		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 30, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		3.3
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
Mutation Taster		=25/75	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80358207; hg19: chr1-35227264;