X-108170621-T-C

Position:

chrX-108170621-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.422

Variant links:

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]

COL4A6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
COL4A6	NM_033641.4 linkuse as main transcript	c.3481A>G	p.Ile1161Val	missense_variant	35/45	ENST00000334504.12	NP_378667.1	Q14031-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A6	ENST00000334504.12 linkuse as main transcript	c.3481A>G	p.Ile1161Val	missense_variant	35/45	5	NM_033641.4	ENSP00000334733.7		Q14031-2

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

4345

AN:

112011

Hom.:

Cov.:

AF XY:

0.0355

AC XY:

1213

AN XY:

34179

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0549

AC XY:

19574

AN XY:

356793

show subpopulations

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.:

Cov.:

AF XY:

0.0355

AC XY:

1214

AN XY:

34244

show subpopulations

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:

ESP6500EA

AF:

0.0632

AC:

425

ExAC

AF:

0.0407

AC:

4939

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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	-	- -

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

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.2

DANN

Benign

0.45

DEOGEN2

Benign

0.27

.;T;.;.;T;T

FATHMM_MKL

Benign

0.031

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

MutationAssessor

Benign

0.39

.;N;.;.;.;.

PrimateAI

Benign

0.28

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over