rs281874735

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000328300.11(COL4A5):c.4316G>A(p.Gly1439Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1439R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

COL4A5
ENST00000328300.11 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 8.66

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 2 uncertain in ENST00000328300.11

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-108686129-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562348.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant X-108687482-G-A is Pathogenic according to our data. Variant chrX-108687482-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 996230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.4316G>A	p.Gly1439Asp	missense_variant, splice_region_variant	49/53	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.4316G>A	p.Gly1439Asp	missense_variant, splice_region_variant	49/53	1	NM_033380.3	ENSP00000331902		P29400-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1095424

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360876

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked Alport syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 21, 2021	Variant summary: COL4A5 c.4298G>A (p.Gly1433Asp) results in a non-conservative amino acid change located in the Collagen triple helix repeat region (IPR008160) of the encoded protein sequence and is predicted to disrupt the Gly-X-Y repeats in the collagenous domain of the collagen IV alpha 5 chain. Most COL4A5 mutations in patients with Alport syndrome have been reported to reside in the collagenous domain (Hertz, 2009 and HGMD database). This is further corroborated by the existence of a different nucleotide change, c.4298G>T (p.Gly1433Val) that has been observed in a patient with Alport syndrome (HGMD database, and Ma_2011, PMID 21505094). Five of five in-silico tools predict a damaging effect of the variant on protein function. This supports the rationale for this variant as being located in a mutational hot spot and/or a critical and well established functional domain of the COL4A5 gene. This variant also alters the conserved first nucleotide of exon 47 adjacent to the preceding intron 46 splice acceptor site of the COL4A5 gene. Several computational tools predict an impact on normal splicing: One predict the variant abolishes the canonical 3' acceptor site. Two predict the variant weakens the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 182609 control chromosomes. To our knowledge, no occurrence of c.4298G>A in individuals affected with Alport Syndrome 1, X-Linked Recessive and no experimental evidence demonstrating its impact on protein function have been reported. Therefore, the impact of this variant on the molecular basis of disease cannot be unequivocally determined. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1433 of the COL4A5 protein (p.Gly1433Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 996230). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). This variant disrupts the p.Gly1433 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 21505094), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.72

BayesDel_noAF

Pathogenic

0.79

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

.;D

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

4.6

.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.2

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.99

MutPred

0.95

.;Loss of catalytic residue at P1429 (P = 0.0946);

MVP

0.98

MPC

1.2

ClinPred

1.0

GERP RS

5.6

Varity_R

0.99

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.11

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