X-108622766-G-T

Position:

chrX-108622766-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_033380.3(COL4A5):c.2858G>T(p.Gly953Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,209,432 control chromosomes in the GnomAD database, including 8 homozygotes. There are 474 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., 71 hem., cov: 23)

Exomes 𝑓: 0.0010 ( 8 hom. 403 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 7.25

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008373588).

BP6

Variant X-108622766-G-T is Benign according to our data. Variant chrX-108622766-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24573.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Uncertain_significance=1}. Variant chrX-108622766-G-T is described in Lovd as [Likely_benign]. Variant chrX-108622766-G-T is described in Lovd as [Pathogenic]. Variant chrX-108622766-G-T is described in Lovd as [Likely_pathogenic]. Variant chrX-108622766-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00158 (178/112480) while in subpopulation EAS AF= 0.0374 (132/3529). AF 95% confidence interval is 0.0322. There are 0 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 71 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.2858G>T	p.Gly953Val	missense_variant	33/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.2858G>T	p.Gly953Val	missense_variant	33/53	1	NM_033380.3	ENSP00000331902		P29400-2
COL4A5	ENST00000483338.1 linkuse as main transcript	c.1682G>T	p.Gly561Val	missense_variant	17/20	1		ENSP00000495685
COL4A5	ENST00000361603.7 linkuse as main transcript	c.2858G>T	p.Gly953Val	missense_variant	33/51	2		ENSP00000354505	P1	P29400-1
COL4A5	ENST00000505728.1 linkuse as main transcript	c.92G>T	p.Gly31Val	missense_variant	1/5	3		ENSP00000424137

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

179

AN:

112429

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

AN XY:

34609

show subpopulations

Gnomad AFR

AF:

0.000646

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000374

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0376

Gnomad SAS

AF:

0.00661

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.00360

AC:

659

AN:

182930

Hom.:

AF XY:

0.00337

AC XY:

228

AN XY:

67596

show subpopulations

Gnomad AFR exome

AF:

0.000533

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0368

Gnomad SAS exome

AF:

0.00650

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00104

AC:

1146

AN:

1096952

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

403

AN XY:

362498

show subpopulations

Gnomad4 AFR exome

AF:

0.000227

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0223

Gnomad4 SAS exome

AF:

0.00529

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000202

Gnomad4 OTH exome

AF:

0.00348

GnomAD4 genome

AF:

0.00158

AC:

178

AN:

112480

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

AN XY:

34670

show subpopulations

Gnomad4 AFR

AF:

0.000645

Gnomad4 AMR

AF:

0.000374

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0374

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00130

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00146

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00342

AC:

415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked Alport syndrome

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2017	p.Gly953Val in exon 33 of COL4A5: This variant is not expected to have clinica l significance, because it has been identified in 3.7% (513/13865) of East Asian chromosomes including 7 homozygotes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104886203, rs78972735). Although it has been reported in several individuals with Alport syndrome or hearing loss, 2 individuals with Alport syndrome had another COL4A5 variant in cis with this va riant, and one individual was reported to have polycystic kidney disease with no additional clinical features of Alport syndrome (Knebelmann 1996, Lennon 2015, Miao 2017, Miyagawa 2013, Nishio 2015, Randles 2016, Tan 2010). In summary, it s frequency is too high to be causative for Alport syndrome. ACMG/AMP criteria a pplied: BA1 -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2019	This variant is associated with the following publications: (PMID: 22995991, 28827396, 30577881, 30367527, 25739341, 23967202, 8940267, 30245029, 31138263, 28476686, 31180159, 32038292) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 24, 2021

- -

COL4A5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.78

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

.;D;D

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0084

T;T;T

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

3.8

H;H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.3

D;D;.

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.0030

D;D;.

Polyphen

1.0

.;D;D

Vest4

0.34

MVP

0.99

MPC

0.37

ClinPred

0.11

GERP RS

6.0

Varity_R

0.99

gMVP

1.0

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