X-108686096-C-T

Position:

chrX-108686096-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_033380.3(COL4A5):c.4282C>T(p.Arg1428Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,208,447 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 340 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.00090 ( 0 hom. 329 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 1.32

Variant links:

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. 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 so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

COL4A5 links:

COL4A5 (HGNC:):

COL4A5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.4282C>T	p.Arg1428Cys	missense_variant	48/53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.4282C>T	p.Arg1428Cys	missense_variant	48/53	1	NM_033380.3	ENSP00000331902.7		P29400-2

Frequencies

GnomAD3 genomes

AF:

0.000351

AC:

AN:

111085

Hom.:

Cov.:

AF XY:

0.000331

AC XY:

AN XY:

33281

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000283

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000168

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000604

Gnomad OTH

AF:

0.000670

GnomAD3 exomes

AF:

0.000345

AC:

AN:

182384

Hom.:

AF XY:

0.000388

AC XY:

AN XY:

67026

show subpopulations

Gnomad AFR exome

AF:

0.000153

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:

0.000188

Gnomad NFE exome

AF:

0.000701

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000900

AC:

988

AN:

1097309

Hom.:

Cov.:

AF XY:

0.000907

AC XY:

329

AN XY:

362753

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.000103

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.000370

Gnomad4 NFE exome

AF:

0.00111

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.000351

AC:

AN:

111138

Hom.:

Cov.:

AF XY:

0.000330

AC XY:

AN XY:

33344

show subpopulations

Gnomad4 AFR

AF:

0.000131

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000284

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000168

Gnomad4 NFE

AF:

0.000604

Gnomad4 OTH

AF:

0.000662

Alfa

AF:

0.000536

Hom.:

Bravo

AF:

0.000431

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7706490, 9195222) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

X-linked Alport syndrome

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 17, 2022	- -

COL4A5-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2023

The COL4A5 c.4264C>T variant is predicted to result in the amino acid substitution p.Arg1422Cys. This variant was reported in two individuals with Alport syndrome along with a second potentially pathogenic variant (Guo. 1995. PubMed ID: 7706490; Table S3, Domingo-Gallego. 2022. PubMed ID: 33532864). This variant is reported in 0.067% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 28 hemizygous individuals (http://gnomad.broadinstitute.org/variant/X-107929326-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;D

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.015

D;D

Sift4G

Benign

0.065

T;T

Polyphen

0.40

.;B

Vest4

0.91

MVP

0.97

MPC

1.2

ClinPred

0.11

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.53

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

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