rs145388022

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_033641.4(COL4A6):c.3760G>T(p.Ala1254Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00945 in 1,207,467 control chromosomes in the GnomAD database, including 78 homozygotes. There are 3,783 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 1 hom., 296 hem., cov: 24)

Exomes 𝑓: 0.0096 ( 77 hom. 3487 hem. )

Consequence

COL4A6
NM_033641.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.168

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005559027).

BP6

Variant X-108165418-C-A is Benign according to our data. Variant chrX-108165418-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 258276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108165418-C-A is described in Lovd as [Benign].

BS2

High Hemizygotes in GnomAd4 at 296 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4 link	c.3760G>T	p.Ala1254Ser	missense_variant	Exon 38 of 45	ENST00000334504.12	NP_378667.1	Q14031-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A6	ENST00000334504.12 link	c.3760G>T	p.Ala1254Ser	missense_variant	Exon 38 of 45	5	NM_033641.4	ENSP00000334733.7		Q14031-2

Frequencies

GnomAD3 genomes

AF:

0.00794

AC:

888

AN:

111771

Hom.:

Cov.:

AF XY:

0.00872

AC XY:

296

AN XY:

33943

show subpopulations

Gnomad AFR

AF:

0.00124

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00132

Gnomad ASJ

AF:

0.00341

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00115

Gnomad FIN

AF:

0.0427

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00396

GnomAD3 exomes

AF:

0.00978

AC:

1757

AN:

179672

Hom.:

AF XY:

0.00955

AC XY:

615

AN XY:

64380

show subpopulations

Gnomad AFR exome

AF:

0.000916

Gnomad AMR exome

AF:

0.000999

Gnomad ASJ exome

AF:

0.00374

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00277

Gnomad FIN exome

AF:

0.0456

Gnomad NFE exome

AF:

0.0111

Gnomad OTH exome

AF:

0.00675

GnomAD4 exome

AF:

0.00961

AC:

10528

AN:

1095642

Hom.:

Cov.:

AF XY:

0.00965

AC XY:

3487

AN XY:

361426

show subpopulations

Gnomad4 AFR exome

AF:

0.00103

Gnomad4 AMR exome

AF:

0.00112

Gnomad4 ASJ exome

AF:

0.00354

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00355

Gnomad4 FIN exome

AF:

0.0415

Gnomad4 NFE exome

AF:

0.00974

Gnomad4 OTH exome

AF:

0.00709

GnomAD4 genome

AF:

0.00794

AC:

888

AN:

111825

Hom.:

Cov.:

AF XY:

0.00870

AC XY:

296

AN XY:

34007

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00132

Gnomad4 ASJ

AF:

0.00341

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00115

Gnomad4 FIN

AF:

0.0427

Gnomad4 NFE

AF:

0.0104

Gnomad4 OTH

AF:

0.00391

Alfa

AF:

0.00943

Hom.:

405

Bravo

AF:

0.00512

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.0107

AC:

ESP6500AA

AF:

0.00261

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.00928

AC:

1127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 01, 2018

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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing loss, X-linked 6

Benign:1

Mar 15, 2022

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

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

.;T;.;.;T;T

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.67

T;T;T;T;T;T

MetaRNN

Benign

0.0056

T;T;T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.055

.;N;.;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

0.19

N;N;.;N;.;.

REVEL

Benign

0.25

Sift

Benign

1.0

T;T;.;T;.;.

Sift4G

Benign

0.96

T;T;T;T;T;T

Polyphen

0.77

P;P;.;B;.;.

Vest4

0.080

MVP

0.63

MPC

0.31

ClinPred

0.024

GERP RS

3.4

Varity_R

0.12

gMVP

0.070

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