rs104894820

chrX-71223744-G-AchrX-71223744-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PM1 PM5 PP3_Strong BS2

The NM_000166.6(GJB1):c.37G>A(p.Val13Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,208,459 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V13L) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 5 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:2
• Conservation: PhyloP100: 9.97

Genes affected

GJB1 (HGNC:4283): (gap junction protein beta 1) This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000166.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71223744-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 10439.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.37G>A	p.Val13Met	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.37G>A	p.Val13Met	missense_variant	2/2
GJB1	XM_011530907.3	c.37G>A	p.Val13Met	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.37G>A	p.Val13Met	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000538 AC: 6 AN: 111534 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33740

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000382

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000602 AC: 11 AN: 182766 Hom.: 0 AF XY: 0.0000297 AC XY: 2 AN XY: 67404

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1096925 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 362319

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000832

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000538 AC: 6 AN: 111534 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33740

Gnomad4 AFR AF: 0.0000326

Gnomad4 AMR AF: 0.000382

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000121

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	The c.37G>A;p.(Val13Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 637129; PMID: 22944031) - PS4_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Connexin) - PM1. The variant is present at low allele frequencies population databases (rs104894820 - gnomAD 0.0006019%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID: 10439 - c.37G>T;p.(Val13Leu); PMID: 27544631 - p.(Val13Glu)) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, flagged submission

literature only

Inherited Neuropathy Consortium

-

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2020

The p.V13M variant (also known as c.37G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 37. The valine at codon 13 is replaced by methionine, an amino acid with highly similar properties. This alteration has been detected in a small number of individuals who are described as carrying a diagnosis of Charcot-Marie-Tooth neuropathy (Bone LJ et al. Neurobiol Dis, 1997;4:221-30; Liu L et al. Clin Genet, 2017 Jun;91:881-891; Panosyan FB et al. Neurology, 2017 Aug;89:927-935). Based on data from gnomAD, the A allele has an overall frequency of 0.006% (11/182,766) total alleles studied, with 2 hemizygotes observed. The highest observed frequency was 0.033% (9/27,415) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth Neuropathy X Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 09, 2023

- -

not provided Benign:1

Likely benign, no assertion criteria provided

provider interpretation

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.70
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;.;.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.7	D;.;D;.;D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;.;D;.;D
Sift4G	Pathogenic	0.0010	D;.;D;.;D;.;D
Polyphen		1.0	D;D;D;D;.;.;D
Vest4		0.89
MutPred		0.95		Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);Gain of disorder (P = 0.0794);
MVP		1.0
MPC		1.8
ClinPred		0.63	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.95
gMVP		0.98

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: rs104894820; hg19: chrX-70443594;