rs2295912

Variant names:

• chrX-108170700-G-A
• rs2295912
• NM_033641.4:c.3402C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033641.4(COL4A6):​c.3402C>T​(p.Ala1134Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,204,103 control chromosomes in the GnomAD database, including 600 homozygotes. There are 11,102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (207 hom., 1616 hem., cov: 24)
  • Exomes 𝑓: 0.027 (393 hom. 9486 hem.)
• Consequence: COL4A6 NM_033641.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0930

Genes affected

COL4A6 (HGNC:2208): (collagen type IV alpha 6 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene, alpha 5 type IV collagen, so that the gene pair shares a common promoter. Deletions in the alpha 5 gene that extend into the alpha 6 gene result in diffuse leiomyomatosis accompanying the X-linked Alport syndrome caused by the deletion in the alpha 5 gene. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-108170700-G-A is Benign according to our data. Variant chrX-108170700-G-A is described in ClinVar as [Benign]. Clinvar id is 258274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.093 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4	c.3402C>T	p.Ala1134Ala	synonymous_variant	Exon 35 of 45	ENST00000334504.12	NP_378667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A6	ENST00000334504.12	c.3402C>T	p.Ala1134Ala	synonymous_variant	Exon 35 of 45	5	NM_033641.4	ENSP00000334733.7

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 5683 AN: 111817 Hom.: 206 Cov.: 24 AF XY: 0.0473 AC XY: 1609 AN XY: 34015

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.0379

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.0804

Gnomad SAS AF: 0.0479

Gnomad FIN AF: 0.00767

Gnomad MID AF: 0.0211

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0559

GnomAD3 exomes AF: 0.0365 AC: 6480 AN: 177302 Hom.: 154 AF XY: 0.0334 AC XY: 2099 AN XY: 62782

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0455

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.0836

Gnomad SAS exome AF: 0.0461

Gnomad FIN exome AF: 0.00631

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0226

GnomAD4 exome AF: 0.0265 AC: 28952 AN: 1092231 Hom.: 393 Cov.: 30 AF XY: 0.0264 AC XY: 9486 AN XY: 358957

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.0458

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.0794

Gnomad4 SAS exome AF: 0.0461

Gnomad4 FIN exome AF: 0.00761

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.0335

GnomAD4 genome AF: 0.0508 AC: 5688 AN: 111872 Hom.: 207 Cov.: 24 AF XY: 0.0474 AC XY: 1616 AN XY: 34080

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0377

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.0801

Gnomad4 SAS AF: 0.0473

Gnomad4 FIN AF: 0.00767

Gnomad4 NFE AF: 0.0184

Gnomad4 OTH AF: 0.0552

Alfa AF: 0.0264 Hom.: 1122

Bravo AF: 0.0580

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing loss, X-linked 6 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.1
DANN	Benign	0.41

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: rs2295912; hg19: chrX-107413930; COSMIC: COSV57861634;