rs104886164

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM5BP4_StrongBS1BS2

The NM_033380.3(COL4A5):c.2215C>G(p.Pro739Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000942 in 1,184,160 control chromosomes in the GnomAD database, including 20 homozygotes. There are 341 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P739S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., 20 hem., cov: 22)

Exomes 𝑓: 0.00098 ( 19 hom. 321 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.09

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 -10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.020849556).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000605 (67/110815) while in subpopulation EAS AF= 0.0174 (61/3505). AF 95% confidence interval is 0.0139. There are 1 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.2215C>G	p.Pro739Ala	missense_variant	28/53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL4A5	ENST00000328300.11 link	c.2215C>G	p.Pro739Ala	missense_variant	28/53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1 link	c.1039C>G	p.Pro347Ala	missense_variant	12/20	1		ENSP00000495685.1	Q49AM6
COL4A5	ENST00000361603.7 link	c.2215C>G	p.Pro739Ala	missense_variant	28/51	2		ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

110770

Hom.:

Cov.:

AF XY:

0.000606

AC XY:

AN XY:

32990

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000192

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0173

Gnomad SAS

AF:

0.000769

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00134

GnomAD3 exomes

AF:

0.00116

AC:

175

AN:

151506

Hom.:

AF XY:

0.000907

AC XY:

AN XY:

47432

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0134

Gnomad SAS exome

AF:

0.000434

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000761

GnomAD4 exome

AF:

0.000976

AC:

1048

AN:

1073345

Hom.:

Cov.:

AF XY:

0.000930

AC XY:

321

AN XY:

345329

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0333

Gnomad4 SAS exome

AF:

0.000425

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000970

Gnomad4 OTH exome

AF:

0.000599

GnomAD4 genome

AF:

0.000605

AC:

AN:

110815

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

33045

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000192

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0174

Gnomad4 SAS

AF:

0.000771

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00132

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.000578

ExAC

AF:

0.00111

AC:

132

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked Alport syndrome

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 28, 2018

- -

COL4A5-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

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

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.91

.;D;D

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.84

T;T;T

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

1.9

M;M;.

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.2

D;D;.

REVEL

Uncertain

0.36

Sift

Benign

0.049

D;T;.

Sift4G

Benign

0.082

T;T;.

Polyphen

0.34, 0.20

.;B;B

Vest4

0.17

MVP

0.86

MPC

0.29

ClinPred

0.066

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.14

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