ENST00000870749.1:c.-713G>A

Variant names:

• chrX-71222995-G-A
• rs6525485
• ENST00000870749.1:c.-713G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The ENST00000870749.1(GJB1):​c.-713G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (17658 hom., 20673 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: GJB1 ENST00000870749.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.80
• Publications: 1 publications found

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]

GJB1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease X-linked dominant 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• X-linked progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-71222995-G-A is Benign according to our data. Variant chrX-71222995-G-A is described in ClinVar as Benign. ClinVar VariationId is 255410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000870749.1. 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
	GJB1	NM_001097642.3		c.-16-697G>A		intron	N/A	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.-17+229G>A		intron	N/A	NP_001427699.1
	GJB1	NM_000166.6	MANE Select	c.-357G>A		upstream_gene	N/A	NP_000157.1	P08034

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000870749.1		c.-713G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000540808.1
	GJB1	ENST00000870756.1		c.-713G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000540815.1
	GJB1	ENST00000870749.1		c.-713G>A		5_prime_UTR	Exon 2 of 2	ENSP00000540808.1

Frequencies

GnomAD3 genomes AF: 0.661 AC: 72306 AN: 109426 Hom.: 17647 Cov.: 22

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.757

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.651

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.661 AC: 72363 AN: 109473 Hom.: 17658 Cov.: 22 AF XY: 0.651 AC XY: 20673 AN XY: 31771

African (AFR) AF: 0.813 AC: 24479 AN: 30094

American (AMR) AF: 0.662 AC: 6798 AN: 10272

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1356 AN: 2619

East Asian (EAS) AF: 0.757 AC: 2580 AN: 3406

South Asian (SAS) AF: 0.568 AC: 1454 AN: 2560

European-Finnish (FIN) AF: 0.621 AC: 3549 AN: 5717

Middle Eastern (MID) AF: 0.621 AC: 131 AN: 211

European-Non Finnish (NFE) AF: 0.584 AC: 30649 AN: 52456

Other (OTH) AF: 0.657 AC: 969 AN: 1476

Alfa AF: 0.581 Hom.: 18384

Bravo AF: 0.674

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Charcot-Marie-Tooth Neuropathy X (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0020
DANN	Benign	0.89
PhyloP100		-3.8
PromoterAI		0.0036	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs6525485; hg19: chrX-70442845;