rs281874743

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_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 (★★).

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

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 links:

COL4A5 (HGNC:):

COL4A5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain Collagen IV NC1 (size 224) in uniprot entity CO4A5_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_033380.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant X-108692925-G-A is Pathogenic according to our data. Variant chrX-108692925-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108692925-G-A is described in Lovd as [Pathogenic]. Variant chrX-108692925-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.4706G>A	p.Arg1569Gln	missense_variant, splice_region_variant	50/53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.4706G>A	p.Arg1569Gln	missense_variant, splice_region_variant	50/53	1	NM_033380.3	ENSP00000331902.7		P29400-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111816

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34002

FAILED QC

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

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000882

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Precision Medicine Center, Zhengzhou University	Dec 01, 2023	PM1,PM2_p,PP1,PP3,PP4 -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Jan 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 20, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2023	ClinVar contains an entry for this variant (Variation ID: 24757). For these reasons, this variant has been classified as Pathogenic. 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. 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. 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. This variant is not present in population databases (gnomAD no frequency). 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. -

Kidney disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 03, 2017

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

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

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 12, 2021

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

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;.

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

Varity_R

0.96

gMVP

0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over