rs80358210

chr1-34761507-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_153212.3(GJB4):c.253A>C(p.Thr85Pro) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB4 NM_153212.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.681

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 1-34761507-A-C is Pathogenic according to our data. Variant chr1-34761507-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 5006.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-34761507-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB4	NM_153212.3	c.253A>C	p.Thr85Pro	missense_variant	2/2	ENST00000339480.3
GJB4	XM_011540679.3	c.253A>C	p.Thr85Pro	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB4	ENST00000339480.3	c.253A>C	p.Thr85Pro	missense_variant	2/2	2	NM_153212.3	P1
	ENST00000542839.1	n.479T>G		non_coding_transcript_exon_variant	2/2	5
SMIM12	ENST00000426886.1	c.208-43098T>G		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2016

The T85P variant has been published previously in a large kindred where the variant was shown to co-segregate with disease in affected family members (Richard et al., 2003). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. T85P is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although this substitution occurs at a position within the second transmembrane region where amino acids with similar properties to Threonine are tolerated across species, in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a missense variant in a nearby residue (C86S) has been reported in the Human Gene Mutation Database in association with erythrokeratodermia variabilis (Stenson et al., 2014), supporting the functional importance of this region of the protein. -

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	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	0.99	A
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.95		Loss of helix (P = 0.1706);
MVP		0.93
MPC		0.53
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.90

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: rs80358210; hg19: chr1-35227108;