rs104886285

Positions:

chrX-108692769-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BS2_Supporting

The NM_033380.3(COL4A5):c.4550G>A(p.Arg1517His) variant causes a missense change. The variant allele was found at a frequency of 0.0000165 in 1,209,389 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000016 ( 0 hom. 3 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.84

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

In a domain Collagen IV NC1 (size 224) in uniprot entity CO4A5_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_033380.3

BS2

High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.4550G>A	p.Arg1517His	missense_variant	50/53	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.4550G>A	p.Arg1517His	missense_variant	50/53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000361603.7 linkuse as main transcript	c.4532G>A	p.Arg1511His	missense_variant	48/51	2		ENSP00000354505.2	P29400-1
COL4A5	ENST00000515658.1 linkuse as main transcript	c.323-3528G>A		intron_variant		5		ENSP00000423520.1	H0Y998
COL4A5	ENST00000510690.2 linkuse as main transcript	n.1044G>A		non_coding_transcript_exon_variant	8/11	4

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111497

Hom.:

Cov.:

AF XY:

0.0000594

AC XY:

AN XY:

33665

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

182911

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67529

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1097892

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363304

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000132

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000154

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111497

Hom.:

Cov.:

AF XY:

0.0000594

AC XY:

AN XY:

33665

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000166

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 25, 2023

Variant summary: COL4A5 c.4532G>A (p.Arg1511His) results in a non-conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 (i.e., 3 heterozygous carriers, including 2 females and 1 male) in 182911 control chromosomes (gnomAD v2, Exomes cohort). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4532G>A has been reported in the literature in individuals affected with Alport Syndrome (e.g., Plant_1999, Cheong_2000, Azaiez_2018, Zhao_2019, Park_2020), however, the variant was also reported in an asymptomatic male (Zhao_2019). Therefore these data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant disrupts type IV collagen heterotrimer formation but was still found to be secreted by cells (e.g., Kobayashi_2008). The following publications have been ascertained in the context of this evaluation (PMID: 30245029, 10684360, 18083113, 32604935, 10094548, 30968591). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;D

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.53

MetaRNN

Uncertain

0.54

D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.4

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.3

N;N

REVEL

Pathogenic

0.79

Sift

Benign

0.041

D;D

Sift4G

Benign

0.11

T;T

Polyphen

0.73

.;P

Vest4

0.33

MVP

0.99

MPC

0.63

ClinPred

0.39

GERP RS

4.8

Varity_R

0.72

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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