X-108601436-G-T

Position:

chrX-108601436-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033380.3(COL4A5):c.1992G>T(p.Lys664Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,204,997 control chromosomes in the GnomAD database, including 59 homozygotes. There are 4,497 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 6 hom., 210 hem., cov: 21)

Exomes 𝑓: 0.012 ( 53 hom. 4287 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.00600

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068911016).

BP6

Variant X-108601436-G-T is Benign according to our data. Variant chrX-108601436-G-T is described in ClinVar as [Benign]. Clinvar id is 24469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108601436-G-T is described in Lovd as [Pathogenic]. Variant chrX-108601436-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00764 (844/110452) while in subpopulation SAS AF= 0.0125 (32/2551). AF 95% confidence interval is 0.0103. There are 6 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.1992G>T	p.Lys664Asn	missense_variant	26/53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.1992G>T	p.Lys664Asn	missense_variant	26/53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1 linkuse as main transcript	c.816G>T	p.Lys272Asn	missense_variant	10/20	1		ENSP00000495685.1	Q49AM6
COL4A5	ENST00000361603.7 linkuse as main transcript	c.1992G>T	p.Lys664Asn	missense_variant	26/51	2		ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes

AF:

0.00764

AC:

844

AN:

110426

Hom.:

Cov.:

AF XY:

0.00642

AC XY:

210

AN XY:

32716

show subpopulations

Gnomad AFR

AF:

0.00211

Gnomad AMI

AF:

0.0846

Gnomad AMR

AF:

0.00375

Gnomad ASJ

AF:

0.00758

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0125

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.0128

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.00952

GnomAD3 exomes

AF:

0.00797

AC:

1441

AN:

180748

Hom.:

AF XY:

0.00882

AC XY:

577

AN XY:

65436

show subpopulations

Gnomad AFR exome

AF:

0.00131

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.00834

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0140

Gnomad FIN exome

AF:

0.00536

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.00739

GnomAD4 exome

AF:

0.0116

AC:

12683

AN:

1094545

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

4287

AN XY:

360643

show subpopulations

Gnomad4 AFR exome

AF:

0.00141

Gnomad4 AMR exome

AF:

0.00316

Gnomad4 ASJ exome

AF:

0.00837

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.0148

Gnomad4 FIN exome

AF:

0.00562

Gnomad4 NFE exome

AF:

0.0129

Gnomad4 OTH exome

AF:

0.00939

GnomAD4 genome

AF:

0.00764

AC:

844

AN:

110452

Hom.:

Cov.:

AF XY:

0.00641

AC XY:

210

AN XY:

32756

show subpopulations

Gnomad4 AFR

AF:

0.00211

Gnomad4 AMR

AF:

0.00375

Gnomad4 ASJ

AF:

0.00758

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0125

Gnomad4 FIN

AF:

0.00555

Gnomad4 NFE

AF:

0.0110

Gnomad4 OTH

AF:

0.00940

Alfa

AF:

0.0105

Hom.:

484

Bravo

AF:

0.00783

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.0131

AC:

ExAC

AF:

0.00792

AC:

962

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2024	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Lys664Asn in exon 26 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 1.47% (127/8628) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs34077552). -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2019	This variant is associated with the following publications: (PMID: 17396119, 11462238, 8940267, 17660027) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2022

- -

X-linked Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Uncertain

0.46

.;T;T

FATHMM_MKL

Benign

0.054

LIST_S2

Uncertain

0.93

D;D;T

MetaRNN

Benign

0.0069

T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.42

N;N;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

N;N;.

REVEL

Benign

0.17

Sift

Benign

0.29

T;T;.

Sift4G

Benign

0.25

T;T;.

Polyphen

0.0

.;B;B

Vest4

0.072

MutPred

0.23

Loss of methylation at K664 (P = 0.0025);Loss of methylation at K664 (P = 0.0025);.;

MVP

0.48

MPC

0.35

ClinPred

0.0015

GERP RS

-0.87

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.63

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