Genetic Variant COL4A6:p.Ser454Thr (chrX-108190458-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033641.4(COL4A6):c.1360T>A(p.Ser454Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S454P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 22)

Failed GnomAD Quality Control

Consequence

COL4A6
NM_033641.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0770

Publications

29 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0845491).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4 link	c.1360T>A	p.Ser454Thr	missense_variant	Exon 20 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.1360T>A	p.Ser454Thr	missense_variant	Exon 20 of 45	5	NM_033641.4	ENSP00000334733.7		Q14031-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

109543

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

109543

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31791

African (AFR)

AF:

0.00

AC:

AN:

30011

American (AMR)

AF:

0.00

AC:

AN:

10262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2602

East Asian (EAS)

AF:

0.00

AC:

AN:

3471

South Asian (SAS)

AF:

0.00

AC:

AN:

2501

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5743

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52567

Other (OTH)

AF:

0.00

AC:

AN:

1475

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.9

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.042

.;T;.;.;T;T

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.020

T;T;T;T;T;T

M_CAP

Benign

0.068

MetaRNN

Benign

0.085

T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

-0.43

.;N;.;.;.;.

PhyloP100

0.077

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.080

N;N;.;N;.;N

REVEL

Benign

0.17

Sift

Benign

0.27

T;T;.;T;.;T

Sift4G

Benign

0.20

T;T;T;T;T;T

Polyphen

0.0

B;B;.;B;.;B

Vest4

0.068

MutPred

0.16

.;Loss of glycosylation at S455 (P = 0.0394);.;.;.;.;

MVP

0.27

MPC

0.16

ClinPred

0.21

GERP RS

0.71

Varity_R

0.065

gMVP

0.29

Mutation Taster

=98/2

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over