rs112034997

Positions:

• chrX-108176874-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_033641.4(COL4A6):​c.2653G>T​(p.Val885Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,209,619 control chromosomes in the GnomAD database, including 5 homozygotes. There are 134 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., 54 hem., cov: 24)
  • Exomes 𝑓: 0.00023 (4 hom. 80 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.509

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064350367).
• BP6: Variant X-108176874-C-A is Benign according to our data. Variant chrX-108176874-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445729.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd4 at 54 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A6	NM_033641.4	c.2653G>T	p.Val885Phe	missense_variant	28/45	ENST00000334504.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A6	ENST00000334504.12	c.2653G>T	p.Val885Phe	missense_variant	28/45	5	NM_033641.4	P4

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 140 AN: 112978 Hom.: 0 Cov.: 24 AF XY: 0.00137 AC XY: 48 AN XY: 35110

Gnomad AFR AF: 0.00405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000836

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000364

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00262

GnomAD3 exomes AF: 0.000409 AC: 74 AN: 180805 Hom.: 0 AF XY: 0.000229 AC XY: 15 AN XY: 65421

Gnomad AFR exome AF: 0.00397

Gnomad AMR exome AF: 0.000778

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: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000233 AC: 255 AN: 1096586 Hom.: 4 Cov.: 30 AF XY: 0.000221 AC XY: 80 AN XY: 362456

Gnomad4 AFR exome AF: 0.00470

Gnomad4 AMR exome AF: 0.000883

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000713

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00132 AC: 149 AN: 113033 Hom.: 1 Cov.: 24 AF XY: 0.00154 AC XY: 54 AN XY: 35175

Gnomad4 AFR AF: 0.00433

Gnomad4 AMR AF: 0.000835

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000365

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00259

Alfa AF: 0.000164 Hom.: 4

Bravo AF: 0.00176

ESP6500AA AF: 0.00443 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000395 AC: 48

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

COL4A6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	0.69
DANN	Benign	0.89
DEOGEN2	Uncertain	0.42	.;T;.;.;T;T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
MetaRNN	Benign	0.0064	T;T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	-0.045	.;N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;N;.;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.085	T;T;.;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T
Polyphen		0.99	D;D;.;D;.;D
Vest4		0.21
MVP		0.42
MPC		0.72
ClinPred		0.062	T
GERP RS		-4.6
Varity_R		0.11
gMVP		0.19

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: rs112034997; hg19: chrX-107420104;