chrX-108692925-G-A

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.4706G>A(p.Arg1569Gln) 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 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. R1569P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)

Failed GnomAD Quality Control

Consequence

COL4A5
NM_033380.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 10.0

Publications

12 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 3 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-108692925-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3235211.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

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

PP5

Variant X-108692925-G-A is Pathogenic according to our data. Variant chrX-108692925-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 24757.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.4706G>A	p.Arg1569Gln	missense_variant, splice_region_variant	Exon 50 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.4706G>A	p.Arg1569Gln	missense_variant, splice_region_variant	Exon 50 of 53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111816

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

111816

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34002

African (AFR)

AF:

0.00

AC:

AN:

30791

American (AMR)

AF:

0.00

AC:

AN:

10500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3553

South Asian (SAS)

AF:

0.00

AC:

AN:

2675

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53125

Other (OTH)

AF:

0.00

AC:

AN:

1499

Alfa

AF:

0.0000386

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked Alport syndrome

Pathogenic:4

Jan 02, 2018

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 23, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.76). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000024757). The variant has been previously reported as de novo in a similarly affected individual (PMID: 30477285). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 01, 2023

Precision Medicine Center, Zhengzhou University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1,PM2_p,PP1,PP3,PP4 -

Dec 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1563 of the COL4A5 protein (p.Arg1563Gln). This variant also falls at the last nucleotide of exon 48, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked dominant Alport syndrome (PMID: 8455372, 30477285). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24757). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jun 29, 2017

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kidney disorder

Pathogenic:1

Apr 03, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

May 08, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4688G>A (p.R1563Q) alteration is located in exon 48 (coding exon 48) of the COL4A5 gene. This alteration results from a G to A substitution at nucleotide position 4688, causing the arginine (R) at amino acid position 1563 to be replaced by a glutamine (Q), however, this change occurs in the last base pair of coding exon48, which makes it likely to have some effect on normal mRNA splicing. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in the heterozygous or hemizygous state in multiple individuals with COL4A5-related Alport syndrome (Zhou, 1993; Hertz, 2001; Gross, 2002; Ars, 2005; Juan-Juan, 2024; Han, 2019; Sun, 2023). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Hearing impairment

Pathogenic:1

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1_Strong, PM2_Moderate, PP4_Moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.73

BayesDel_noAF

Pathogenic

0.81

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

.;D;.

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

.;M;.

PhyloP100

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.90

MutPred

0.97

.;Loss of sheet (P = 0.0817);.;

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

5.8

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.96

gMVP

0.96

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.77

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.77

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