Variant X-108157124-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_033641.4(COL4A6):c.4949G>A(p.Ser1650Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000281 in 1,210,546 control chromosomes in the GnomAD database, including 1 homozygotes. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 1 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000018 ( 0 hom. 5 hem. )

Consequence

COL4A6
NM_033641.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.16

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34308803).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A6	NM_033641.4 linkuse as main transcript	c.4949G>A	p.Ser1650Asn	missense_variant	45/45	ENST00000334504.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A6	ENST00000334504.12 linkuse as main transcript	c.4949G>A	p.Ser1650Asn	missense_variant	45/45	5	NM_033641.4	P4	Q14031-2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

112338

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

34492

show subpopulations

Gnomad AFR

AF:

0.000453

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

GnomAD3 exomes

AF:

0.0000545

AC:

AN:

183424

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67878

show subpopulations

Gnomad AFR exome

AF:

0.000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1098208

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363564

show subpopulations

Gnomad4 AFR exome

AF:

0.000758

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000125

AC:

AN:

112338

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

34492

show subpopulations

Gnomad4 AFR

AF:

0.000453

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000115

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.4952G>A (p.S1651N) alteration is located in exon 45 (coding exon 45) of the COL4A6 gene. This alteration results from a G to A substitution at nucleotide position 4952, causing the serine (S) at amino acid position 1651 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

0.99

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.34

T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.0

D;D;.;D;.;.

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;D;.;D;.;.

Vest4

0.43

MVP

0.90

MPC

0.17

ClinPred

0.44

GERP RS

4.5

Varity_R

0.82

gMVP

0.97

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

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