X-108580548-C-T

Position:

• chrX-108580548-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.796C>T​(p.Arg266*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.18

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108580548-C-T is Pathogenic according to our data. Variant chrX-108580548-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 24325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108580548-C-T is described in Lovd as [Pathogenic]. Variant chrX-108580548-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.796C>T	p.Arg266*	stop_gained	14/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.796C>T	p.Arg266*	stop_gained	14/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000361603.7	c.796C>T	p.Arg266*	stop_gained	14/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15780079, 25525159, 15954103, 17396119) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 09, 2023	This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 15780079, 17396119, 29854973). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 24325). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg266*) in the COL4A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). -

X-linked Alport syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 30, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Alport syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Sep 10, 2018

This patient is heterozygous for a known pathogenic variant, c.796C>T, in the COL4A5 gene. This variant (dbSNP: rs104886071) creates a premature stop codon (p.Arg266*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been previously reported in the COL4A5 Alport database (http://www.arup.utah.edu/database/ALPORT/ALPORT_welcome.php) and is considered to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.75	D
Vest4		0.90
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs104886071; hg19: chrX-107823778;