NM_033380.3:c.2678G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5

The NM_033380.3(COL4A5):c.2678G>A(p.Gly893Asp) 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G893A) has been classified as 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

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

Conservation

PhyloP100: 9.20

Publications

0 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 10 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 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-108621803-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 988158.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. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant X-108621803-G-A is Pathogenic according to our data. Variant chrX-108621803-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2627505.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.2678G>A	p.Gly893Asp	missense_variant, splice_region_variant	Exon 32 of 53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL4A5	ENST00000328300.11 link	c.2678G>A	p.Gly893Asp	missense_variant, splice_region_variant	Exon 32 of 53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1 link	c.1502G>A	p.Gly501Asp	missense_variant, splice_region_variant	Exon 16 of 20	1		ENSP00000495685.1	Q49AM6
COL4A5	ENST00000361603.7 link	c.2678G>A	p.Gly893Asp	missense_variant, splice_region_variant	Exon 32 of 51	2		ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1081658

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

348492

African (AFR)

AF:

0.00

AC:

AN:

26125

American (AMR)

AF:

0.00

AC:

AN:

35148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19258

East Asian (EAS)

AF:

0.00

AC:

AN:

30111

South Asian (SAS)

AF:

0.00

AC:

AN:

53443

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40469

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4089

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

827492

Other (OTH)

AF:

0.00

AC:

AN:

45523

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Dec 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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 893 of the COL4A5 protein (p.Gly893Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL4A5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

X-linked Alport syndrome

Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant p.G893D in COL4A5 (NM_000495.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.G893D variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The gene COL4A5 contains 202 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.G893D missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.2678 in COL4A5 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.74

BayesDel_noAF

Pathogenic

0.82

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

.;D;D

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.8

H;H;.

PhyloP100

9.2

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.1

D;D;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

.;D;D

Vest4

0.99

MutPred

1.0

Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);.;

MVP

1.0

MPC

0.39

ClinPred

1.0

GERP RS

5.7

Varity_R

1.0

gMVP

1.0

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.44

Position offset: 0

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