rs35179844

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.3373C>T(p.Pro1125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,210,551 control chromosomes in the GnomAD database, including 317 homozygotes. There are 2,183 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 167 hom., 1068 hem., cov: 23)

Exomes 𝑓: 0.0038 ( 150 hom. 1115 hem. )

Consequence

COL4A6
NM_033641.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.88

Publications

4 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=0.0035195649).

BP6

Variant X-108170822-G-A is Benign according to our data. Variant chrX-108170822-G-A is described in ClinVar as Benign. ClinVar VariationId is 258273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4 link	c.3373C>T	p.Pro1125Ser	missense_variant	Exon 34 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.3373C>T	p.Pro1125Ser	missense_variant	Exon 34 of 45	5	NM_033641.4	ENSP00000334733.7		Q14031-2

Frequencies

GnomAD3 genomes

AF:

0.0344

AC:

3883

AN:

112729

Hom.:

167

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00109

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000506

Gnomad OTH

AF:

0.0262

GnomAD2 exomes

AF:

0.0105

AC:

1919

AN:

183216

AF XY:

0.00700

show subpopulations

Gnomad AFR exome

AF:

0.127

Gnomad AMR exome

AF:

0.00740

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000294

Gnomad OTH exome

AF:

0.00420

GnomAD4 exome

AF:

0.00375

AC:

4122

AN:

1097769

Hom.:

150

Cov.:

AF XY:

0.00307

AC XY:

1115

AN XY:

363127

show subpopulations

African (AFR)

AF:

0.123

AC:

3247

AN:

26398

American (AMR)

AF:

0.00824

AC:

290

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.000351

AC:

AN:

54131

European-Finnish (FIN)

AF:

0.0000493

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.00556

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.000177

AC:

149

AN:

841704

Other (OTH)

AF:

0.00851

AC:

392

AN:

46084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

156

311

467

622

778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.0345

AC:

3896

AN:

112782

Hom.:

167

Cov.:

AF XY:

0.0306

AC XY:

1068

AN XY:

34948

show subpopulations

African (AFR)

AF:

0.119

AC:

3685

AN:

31014

American (AMR)

AF:

0.0131

AC:

141

AN:

10742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3567

South Asian (SAS)

AF:

0.000727

AC:

AN:

2751

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6271

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000506

AC:

AN:

53326

Other (OTH)

AF:

0.0259

AC:

AN:

1545

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

128

257

385

514

642

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0135

Hom.:

885

Bravo

AF:

0.0400

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.121

AC:

463

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0113

AC:

1377

EpiCase

AF:

0.000600

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

May 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.085

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Uncertain

0.43

.;T;.;.;T;T

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.79

T;T;D;D;T;T

MetaRNN

Benign

0.0035

T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.5

.;L;.;.;.;.

PhyloP100

1.9

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.5

N;N;.;N;.;N

REVEL

Uncertain

0.29

Sift

Benign

0.42

T;T;.;T;.;T

Sift4G

Benign

0.10

T;T;D;D;T;T

Polyphen

0.12

B;B;.;B;.;B

Vest4

0.099

MPC

0.50

ClinPred

0.0078

GERP RS

2.3

Varity_R

0.044

gMVP

0.57

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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