X-108655431-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_033380.3(COL4A5):c.3347G>T(p.Gly1116Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,687 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 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. G1116R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.31

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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-108655430-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1412256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.996

PP5

Variant X-108655431-G-T is Pathogenic according to our data. Variant chrX-108655431-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 24621.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.3347G>T	p.Gly1116Val	missense_variant	Exon 37 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.3347G>T	p.Gly1116Val	missense_variant	Exon 37 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000361603.7 link	c.3347G>T	p.Gly1116Val	missense_variant	Exon 37 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097687

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363219

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26373

American (AMR)

AF:

0.00

AC:

AN:

35139

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19373

East Asian (EAS)

AF:

0.00

AC:

AN:

30191

South Asian (SAS)

AF:

0.00

AC:

AN:

54135

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4008

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841919

Other (OTH)

AF:

0.00

AC:

AN:

46057

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked Alport syndrome

Pathogenic:3

Apr 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genomic Medicine Lab, University of California San Francisco

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2017

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

COL4A5-related disorder

Pathogenic:1

Dec 13, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The COL4A5 c.3347G>T variant is predicted to result in the amino acid substitution p.Gly1116Val. This variant was reported in at least one individual presenting with microhematuria (Family 53, Table S1, Bekheirnia et al 2010. PubMed ID: 20378821). This variant has not been reported in a large population database, indicating this variant is rare. The p.Gly1116 residue resides in the triple-helical region (residues 42 – 1456) of the COL4A5 protein (uniprot.org). The majority of pathogenic variants in COL4A5 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.72

BayesDel_noAF

Pathogenic

0.80

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

.;D

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

4.4

H;H

PhyloP100

7.3

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-8.3

D;D

REVEL

Pathogenic

0.99

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.99

MutPred

0.99

Loss of catalytic residue at P1112 (P = 0.0722);Loss of catalytic residue at P1112 (P = 0.0722);

MVP

1.0

MPC

0.37

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

1.0

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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