X-108591223-T-G

Position:

chrX-108591223-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_033380.3(COL4A5):c.1331T>G(p.Ile444Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,206,143 control chromosomes in the GnomAD database, including 2,714 homozygotes. There are 8,304 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I444V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.10 ( 1300 hom., 3262 hem., cov: 23)

Exomes 𝑓: 0.016 ( 1414 hom. 5042 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.10

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 -18 ACMG points.

PM1

In a compositionally_biased_region Pro residues (size 47) in uniprot entity CO4A5_HUMAN there are 20 pathogenic changes around while only 6 benign (77%) in NM_033380.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0024892688).

BP6

Variant X-108591223-T-G is Benign according to our data. Variant chrX-108591223-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 24398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108591223-T-G is described in Lovd as [Pathogenic]. Variant chrX-108591223-T-G is described in Lovd as [Likely_benign]. Variant chrX-108591223-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.1331T>G	p.Ile444Ser	missense_variant	20/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.1331T>G	p.Ile444Ser	missense_variant	20/53	1	NM_033380.3		P29400-2
COL4A5	ENST00000483338.1 linkuse as main transcript	c.155T>G	p.Ile52Ser	missense_variant	4/20	1
COL4A5	ENST00000361603.7 linkuse as main transcript	c.1331T>G	p.Ile444Ser	missense_variant	20/51	2		P1	P29400-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

11646

AN:

111986

Hom.:

1300

Cov.:

AF XY:

0.0950

AC XY:

3247

AN XY:

34186

show subpopulations

Gnomad AFR

AF:

0.336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0554

Gnomad ASJ

AF:

0.00301

Gnomad EAS

AF:

0.143

Gnomad SAS

AF:

0.0206

Gnomad FIN

AF:

0.000163

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00130

Gnomad OTH

AF:

0.0894

GnomAD3 exomes

AF:

0.0447

AC:

8115

AN:

181571

Hom.:

685

AF XY:

0.0334

AC XY:

2228

AN XY:

66621

show subpopulations

Gnomad AFR exome

AF:

0.340

Gnomad AMR exome

AF:

0.0431

Gnomad ASJ exome

AF:

0.00351

Gnomad EAS exome

AF:

0.149

Gnomad SAS exome

AF:

0.0171

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000851

Gnomad OTH exome

AF:

0.0240

GnomAD4 exome

AF:

0.0160

AC:

17507

AN:

1094106

Hom.:

1414

Cov.:

AF XY:

0.0140

AC XY:

5042

AN XY:

360496

show subpopulations

Gnomad4 AFR exome

AF:

0.340

Gnomad4 AMR exome

AF:

0.0466

Gnomad4 ASJ exome

AF:

0.00362

Gnomad4 EAS exome

AF:

0.123

Gnomad4 SAS exome

AF:

0.0151

Gnomad4 FIN exome

AF:

0.000173

Gnomad4 NFE exome

AF:

0.000602

Gnomad4 OTH exome

AF:

0.0395

GnomAD4 genome

AF:

0.104

AC:

11658

AN:

112037

Hom.:

1300

Cov.:

AF XY:

0.0952

AC XY:

3262

AN XY:

34247

show subpopulations

Gnomad4 AFR

AF:

0.336

Gnomad4 AMR

AF:

0.0552

Gnomad4 ASJ

AF:

0.00301

Gnomad4 EAS

AF:

0.143

Gnomad4 SAS

AF:

0.0203

Gnomad4 FIN

AF:

0.000163

Gnomad4 NFE

AF:

0.00130

Gnomad4 OTH

AF:

0.0883

Alfa

AF:

0.0201

Hom.:

620

Bravo

AF:

0.120

ESP6500AA

AF:

0.332

AC:

1273

ESP6500EA

AF:

0.00164

AC:

ExAC

AF:

0.0468

AC:

5678

EpiCase

AF:

0.000819

EpiControl

AF:

0.000831

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 22, 2017	p.Ile444Ser in exon 20 of COL4A5: This variant is not expected to have clinical significance because it has been identified in 34% (6123/17969) of African chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs2272946). ACMG/AMP Criteria applied: BA1. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

X-linked Alport syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 21, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 8648925, 27884173, 11223851, 10561141, 8940267, 30245029) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.2

DANN

Benign

0.65

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.56

T;T;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;.

MutationTaster

Benign

1.0e-37

P;P

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.18

N;N;.

REVEL

Benign

0.23

Sift

Benign

0.56

T;T;.

Sift4G

Benign

0.40

T;T;.

Polyphen

0.017, 0.040

.;B;B

Vest4

0.11

MPC

0.44

ClinPred

0.0032

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.16

gMVP

0.78

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