dbSNP rs773883586: COL4A5:p.Pro88Thr (chrX-108563912-C-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_033380.3(COL4A5):c.262C>A(p.Pro88Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P88S) has been classified as Benign.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.86

Publications

3 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: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a compositionally_biased_region Pro residues (size 18) in uniprot entity CO4A5_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_033380.3

PM2

Very rare variant in population databases, with high coverage;

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.262C>A	p.Pro88Thr	missense_variant	Exon 4 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.262C>A	p.Pro88Thr	missense_variant	Exon 4 of 53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000361603.7 link	c.262C>A	p.Pro88Thr	missense_variant	Exon 4 of 51	2		ENSP00000354505.2	P29400-1
COL4A5	ENST00000470339.1 link	n.446C>A		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1091334

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

357300

African (AFR)

AF:

0.00

AC:

AN:

26273

American (AMR)

AF:

0.00

AC:

AN:

35135

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19284

East Asian (EAS)

AF:

0.00

AC:

AN:

30051

South Asian (SAS)

AF:

0.00

AC:

AN:

53419

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40453

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4111

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

836791

Other (OTH)

AF:

0.00

AC:

AN:

45817

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.29

DEOGEN2

Uncertain

0.52

.;D

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.75

T;T

M_CAP

Pathogenic

0.68

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

3.9

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.5

N;N

REVEL

Uncertain

0.45

Sift

Benign

1.0

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.23

.;B

Vest4

0.55

MutPred

0.30

Gain of phosphorylation at P88 (P = 0.012);Gain of phosphorylation at P88 (P = 0.012);

MVP

0.77

MPC

0.33

ClinPred

0.95

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.52

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over