rs34466065

chrX-108170621-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033641.4(COL4A6):c.3481A>G(p.Ile1161Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0542 in 1,201,111 control chromosomes in the GnomAD database, including 1,369 homozygotes. There are 20,788 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (74 hom., 1214 hem., cov: 23)
  • Exomes 𝑓: 0.056 (1295 hom. 19574 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.422

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030541122).
• BP6: Variant X-108170621-T-C is Benign according to our data. Variant chrX-108170621-T-C is described in ClinVar as [Benign]. Clinvar id is 258275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A6	NM_033641.4	c.3481A>G	p.Ile1161Val	missense_variant	35/45	ENST00000334504.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A6	ENST00000334504.12	c.3481A>G	p.Ile1161Val	missense_variant	35/45	5	NM_033641.4	P4

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 4345 AN: 112011 Hom.: 74 Cov.: 23 AF XY: 0.0355 AC XY: 1213 AN XY: 34179

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.0146

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0442

Gnomad EAS AF: 0.000559

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0366

Gnomad MID AF: 0.0513

Gnomad NFE AF: 0.0622

Gnomad OTH AF: 0.0441

GnomAD3 exomes AF: 0.0405 AC: 7050 AN: 174213 Hom.: 123 AF XY: 0.0409 AC XY: 2500 AN XY: 61111

Gnomad AFR exome AF: 0.00887

Gnomad AMR exome AF: 0.0215

Gnomad ASJ exome AF: 0.0436

Gnomad EAS exome AF: 0.000151

Gnomad SAS exome AF: 0.0189

Gnomad FIN exome AF: 0.0435

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0508

GnomAD4 exome AF: 0.0558 AC: 60752 AN: 1089045 Hom.: 1295 Cov.: 30 AF XY: 0.0549 AC XY: 19574 AN XY: 356793

Gnomad4 AFR exome AF: 0.00780

Gnomad4 AMR exome AF: 0.0231

Gnomad4 ASJ exome AF: 0.0431

Gnomad4 EAS exome AF: 0.000166

Gnomad4 SAS exome AF: 0.0205

Gnomad4 FIN exome AF: 0.0433

Gnomad4 NFE exome AF: 0.0636

Gnomad4 OTH exome AF: 0.0521

GnomAD4 genome AF: 0.0388 AC: 4346 AN: 112066 Hom.: 74 Cov.: 23 AF XY: 0.0355 AC XY: 1214 AN XY: 34244

Gnomad4 AFR AF: 0.00860

Gnomad4 AMR AF: 0.0290

Gnomad4 ASJ AF: 0.0442

Gnomad4 EAS AF: 0.000561

Gnomad4 SAS AF: 0.0147

Gnomad4 FIN AF: 0.0366

Gnomad4 NFE AF: 0.0622

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0577 Hom.: 2690

Bravo AF: 0.0360

TwinsUK AF: 0.0553 AC: 205

ALSPAC AF: 0.0585 AC: 169

ESP6500AA AF: 0.0107 AC: 41

ESP6500EA AF: 0.0632 AC: 425

ExAC AF: 0.0407 AC: 4939

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -

Hearing loss, X-linked 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	1.2
Dann	Benign	0.45
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.76	T;T;D;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.63	N;N;.;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.58	T;T;.;T;.;T
Sift4G	Benign	0.36	T;T;T;T;T;T
Polyphen		0.015	B;B;.;B;.;B
Vest4		0.048
MPC		0.20
ClinPred		0.0025	T
GERP RS		-2.0
Varity_R		0.038
gMVP		0.37

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: rs34466065; hg19: chrX-107413851;