rs104886059

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_033380.3(COL4A5):c.548G>A(p.Gly183Asp) 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. 3/3 splice prediction tools predict no significant impact on 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. G183V) 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: 0.9206

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.90

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 13 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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-108575911-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3597862.Status of the report is criteria_provided_single_submitter, 1 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

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant X-108575911-G-A is Pathogenic according to our data. Variant chrX-108575911-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1687242.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.548G>A	p.Gly183Asp	missense_variant, splice_region_variant	Exon 10 of 53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 link	c.548G>A	p.Gly183Asp	missense_variant, splice_region_variant	Exon 10 of 53	1	NM_033380.3	ENSP00000331902.7		P29400-2
COL4A5	ENST00000361603.7 link	c.548G>A	p.Gly183Asp	missense_variant, splice_region_variant	Exon 10 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:

1056135

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

330501

African (AFR)

AF:

0.00

AC:

AN:

25496

American (AMR)

AF:

0.00

AC:

AN:

34758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19005

East Asian (EAS)

AF:

0.00

AC:

AN:

29698

South Asian (SAS)

AF:

0.00

AC:

AN:

52177

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4042

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

806419

Other (OTH)

AF:

0.00

AC:

AN:

44580

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked Alport syndrome

Pathogenic:1

May 22, 2022

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.95). Different missense changes at the same codon (p.Gly183Ser, p.Gly183Val) have been reported to be associated with COL4A5 related disorder (ClinVar ID: VCV000438706 / PMID: 15954103). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.71

BayesDel_noAF

Pathogenic

0.78

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

.;D

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

H;H

PhyloP100

7.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0050

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.98

MutPred

0.99

Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);

MVP

0.99

MPC

0.39

ClinPred

1.0

GERP RS

5.5

Varity_R

1.0

gMVP

1.0

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Benign

0.47

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

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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