rs35363062

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033641.4(COL4A6):c.4082T>C(p.Leu1361Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,193,027 control chromosomes in the GnomAD database, including 197 homozygotes. There are 1,639 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 99 hom., 796 hem., cov: 23)

Exomes 𝑓: 0.0030 ( 98 hom. 843 hem. )

Consequence

COL4A6
NM_033641.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.429

Publications

2 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026853085).

BP6

Variant X-108163026-A-G is Benign according to our data. Variant chrX-108163026-A-G is described in ClinVar as Benign. ClinVar VariationId is 258278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4 link	c.4082T>C	p.Leu1361Pro	missense_variant	Exon 41 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.4082T>C	p.Leu1361Pro	missense_variant	Exon 41 of 45	5	NM_033641.4	ENSP00000334733.7		Q14031-2

Frequencies

GnomAD3 genomes

AF:

0.0281

AC:

3126

AN:

111284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0980

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00873

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00115

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000321

Gnomad OTH

AF:

0.0194

GnomAD2 exomes

AF:

0.00844

AC:

1369

AN:

162253

AF XY:

0.00459

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.00521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000147

Gnomad OTH exome

AF:

0.00309

GnomAD4 exome

AF:

0.00304

AC:

3289

AN:

1081691

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

843

AN XY:

351539

show subpopulations

African (AFR)

AF:

0.105

AC:

2650

AN:

25317

American (AMR)

AF:

0.00625

AC:

199

AN:

31856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18828

East Asian (EAS)

AF:

0.00

AC:

AN:

28835

South Asian (SAS)

AF:

0.000255

AC:

AN:

50884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40370

Middle Eastern (MID)

AF:

0.00344

AC:

AN:

4064

European-Non Finnish (NFE)

AF:

0.000123

AC:

103

AN:

836071

Other (OTH)

AF:

0.00682

AC:

310

AN:

45466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

117

234

351

468

585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0282

AC:

3138

AN:

111336

Hom.:

Cov.:

AF XY:

0.0237

AC XY:

796

AN XY:

33566

show subpopulations

African (AFR)

AF:

0.0982

AC:

2998

AN:

30529

American (AMR)

AF:

0.00872

AC:

AN:

10551

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3541

South Asian (SAS)

AF:

0.000766

AC:

AN:

2610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6079

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000321

AC:

AN:

52972

Other (OTH)

AF:

0.0192

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

110

219

329

438

548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0108

Hom.:

518

Bravo

AF:

0.0335

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.105

AC:

403

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00954

AC:

1158

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 08, 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. -

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

0.050

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.44

CADD

Benign

6.0

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.24

.;T;.;.;T;T

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.46

T;T;T;T;T;T

MetaRNN

Benign

0.0027

T;T;T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

-1.4

.;N;.;.;.;.

PhyloP100

-0.43

PrimateAI

Benign

0.32

PROVEAN

Benign

0.68

N;N;.;N;.;.

REVEL

Benign

0.16

Sift

Benign

0.49

T;T;.;T;.;.

Sift4G

Benign

0.43

T;T;T;T;T;T

Polyphen

0.0040

B;B;.;B;.;.

Vest4

0.082

MVP

0.12

MPC

0.29

ClinPred

0.00056

GERP RS

1.4

Varity_R

0.059

gMVP

0.21

Mutation Taster

=100/0

polymorphism (auto)

(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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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