rs112034997

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. 13/20 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.509

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hearing loss, X-linked 6
Inheritance: XL Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, PanelApp Australia
X-linked nonsyndromic hearing loss
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
premature ovarian failure 1
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

COL4A6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High Hemizygotes in GnomAd4 at 54 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4 link	c.2653G>T	p.Val885Phe	missense_variant	Exon 28 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.2653G>T	p.Val885Phe	missense_variant	Exon 28 of 45	5	NM_033641.4	ENSP00000334733.7		Q14031-2

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

140

AN:

112978

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000409

AC:

AN:

180805

AF XY:

0.000229

show subpopulations

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 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.:

Cov.:

AF XY:

0.000221

AC XY:

AN XY:

362456

show subpopulations

African (AFR)

AF:

0.00470

AC:

124

AN:

26357

American (AMR)

AF:

0.000883

AC:

AN:

35125

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19324

East Asian (EAS)

AF:

0.00

AC:

AN:

30166

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53870

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3494

European-Non Finnish (NFE)

AF:

0.00000713

AC:

AN:

841743

Other (OTH)

AF:

0.00202

AC:

AN:

45995

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00132

AC:

149

AN:

113033

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

AN XY:

35175

show subpopulations

African (AFR)

AF:

0.00433

AC:

135

AN:

31155

American (AMR)

AF:

0.000835

AC:

AN:

10774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.000365

AC:

AN:

2739

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6279

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53404

Other (OTH)

AF:

0.00259

AC:

AN:

1547

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000247

Hom.:

Bravo

AF:

0.00176

ESP6500AA

AF:

0.00443

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000395

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Apr 11, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

COL4A6-related disorder

Benign:1

Jun 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.35

CADD

Benign

0.69

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.42

.;T;.;.;T;T

FATHMM_MKL

Benign

0.13

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

MutationAssessor

Benign

-0.045

.;N;.;.;.;.

PhyloP100

-0.51

PrimateAI

Benign

0.31

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

GERP RS

-4.6

Varity_R

0.11

gMVP

0.19

Mutation Taster

=99/1

polymorphism

(source)

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

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rs112034997

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over