rs281874735

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_033380.3(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. 14/23 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
NM_033380.3 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

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Alport syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
X-linked Alport syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

COL4A5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 2 uncertain in NM_033380.3

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 VariationId is 562348.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.4316G>A	p.Gly1439Asp	missense_variant, splice_region_variant	Exon 49 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 link	c.4316G>A	p.Gly1439Asp	missense_variant, splice_region_variant	Exon 49 of 53	1	NM_033380.3	ENSP00000331902.7

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

African (AFR)

AF:

0.00

AC:

AN:

26344

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19371

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54077

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40529

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4091

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839625

Other (OTH)

AF:

0.00

AC:

AN:

45979

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

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 21, 2021

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

not provided

Pathogenic:1

Jul 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;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

Benign

0.0

.;H

PhyloP100

8.7

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

Vest4

0.99

ClinPred

1.0

GERP RS

5.6

Varity_R

0.99

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over