rs80358206

Variant names:

• chr1-34761665-C-A
• rs80358206
• NM_153212.3:c.411C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-34761665-C-A
• chr1-34761665-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1 PM2 PP3_Moderate PP5

The NM_153212.3(GJB4):​c.411C>A​(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 Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely 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: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.59
• Publications: 3 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: Likely_pathogenic. The variant received 9 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, 0.897
• PP5: Variant 1-34761665-C-A is Pathogenic according to our data. Variant chr1-34761665-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 5005.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153212.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB4	NM_153212.3	MANE Select	c.411C>A	p.Phe137Leu	missense	Exon 2 of 2	NP_694944.1	Q9NTQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB4	ENST00000339480.3	TSL:2 MANE Select	c.411C>A	p.Phe137Leu	missense	Exon 2 of 2	ENSP00000345868.1	Q9NTQ9
	SMIM12	ENST00000426886.1	TSL:1	n.208-43256G>T		intron	N/A	ENSP00000429902.1	E5RH51
	GJB4	ENST00000919353.1		c.411C>A	p.Phe137Leu	missense	Exon 2 of 2	ENSP00000589412.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Erythrokeratodermia variabilis et progressiva 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.69
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		0.91	D
GERP RS		5.7
Varity_R		0.59
gMVP		0.72
Mutation Taster		=37/63	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: rs80358206; hg19: chr1-35227266;