rs190676487

Positions:

• chrX-71223275-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000166.6(GJB1):​c.-77G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 237,901 control chromosomes in the GnomAD database, including 8 homozygotes. There are 158 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., 138 hem., cov: 22)
  • Exomes 𝑓: 0.00072 (1 hom. 20 hem.)
• Consequence: GJB1 NM_000166.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.25

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-71223275-G-A is Benign according to our data. Variant chrX-71223275-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 384473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00469 (523/111606) while in subpopulation AFR AF= 0.0157 (483/30731). AF 95% confidence interval is 0.0146. There are 7 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.-77G>A		5_prime_UTR_variant	1/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.-16-417G>A		intron_variant			NP_001091111.1
GJB1	XM_011530907.3	c.-16-417G>A		intron_variant			XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.-77G>A		5_prime_UTR_variant	1/2	1	NM_000166.6	ENSP00000354900	P1

Frequencies

GnomAD3 genomes AF: 0.00464 AC: 518 AN: 111554 Hom.: 7 Cov.: 22 AF XY: 0.00397 AC XY: 134 AN XY: 33732

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

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: 0.000264

Gnomad OTH AF: 0.00267

GnomAD4 exome AF: 0.000721 AC: 91 AN: 126295 Hom.: 1 Cov.: 0 AF XY: 0.000567 AC XY: 20 AN XY: 35283

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.000740

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000728

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.000561

GnomAD4 genome AF: 0.00469 AC: 523 AN: 111606 Hom.: 7 Cov.: 22 AF XY: 0.00408 AC XY: 138 AN XY: 33794

Gnomad4 AFR AF: 0.0157

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000264

Gnomad4 OTH AF: 0.00264

Alfa AF: 0.00463 Hom.: 13

Bravo AF: 0.00530

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.83

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: rs190676487; hg19: chrX-70443125;