rs281874753

Variant names:

• chrX-108696340-C-T
• rs281874753
• NM_033380.3:c.5038C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.5038C>T​(p.Arg1680*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000912 in 1,096,247 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.01

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00749 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108696340-C-T is Pathogenic according to our data. Variant chrX-108696340-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 24785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108696340-C-T is described in Lovd as [Pathogenic]. Variant chrX-108696340-C-T is described in Lovd as [Pathogenic]. Variant chrX-108696340-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.5038C>T	p.Arg1680*	stop_gained	Exon 53 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.5038C>T	p.Arg1680*	stop_gained	Exon 53 of 53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096247 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 361745

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1674*) in the COL4A5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 12 amino acid(s) of the COL4A5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 12105244, 20378821, 30577881). This variant is also known as p.Arg1680*. ClinVar contains an entry for this variant (Variation ID: 24785). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the COL4A5 protein in which other variant(s) (p.Arg1677*) have been determined to be pathogenic (PMID: 10094548, 12796257, 19728970, 19965530). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 12 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12105244, 30577881, 20378821, 30586318) -

X-linked Alport syndrome Pathogenic:2

Dec 06, 2018

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome Pathogenic:1

-

Department of Traditional Chinese Medicine, Fujian Provincial Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

In a male patient with Alport syndrome, we found the mutant c.5038C>T (p.Arg1680Ter), which results in a shortened protein that causes illness. His renal pathology showed negative type IV collagen staining for alpha 3 and alpha 5, focal foamy cells in the renal interstitium, and stratified alterations in the basement membrane on electron microscopy, all of which were thought to be signs of renal damage associated with X-linked Alport syndrome. Furthermore, numerous investigations have established the pathogenicity of this mutant location (PMID: 10094548, 12796257, 19728970, 19965530). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
Vest4		0.66
GERP RS		5.8

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

LitVar

Other links and lift over

dbSNP: rs281874753; hg19: chrX-107939570;