2-227056022-GC-G

Position:

chr2-227056022-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000092.5(COL4A4):c.2638del(p.Ala880HisfsTer70) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,612,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

COL4A4
NM_000092.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -0.262

Variant links:

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 2-227056022-GC-G is Pathogenic according to our data. Variant chr2-227056022-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 550471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227056022-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5 linkuse as main transcript	c.2638del	p.Ala880HisfsTer70	frameshift_variant	30/48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 linkuse as main transcript	c.2638del	p.Ala880HisfsTer70	frameshift_variant	30/48	5	NM_000092.5	ENSP00000379866	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249178

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135292

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460612

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726724

show subpopulations

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:

0.0000243

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alport syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 11, 2023	This sequence change in COL4A4 is a frameshift variant predicted to cause a premature stop codon, p.(Ala880Hisfs*70), in biologically relevant exon 31/48 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism (PMID: 20301386). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (2/15,438 alleles) in the African/African American population. This variant has been detected in at least two unrelated individuals with Alport syndrome. Of those individuals, one individual was homozygous and one compound heterozygous for the variant and a pathogenic variant was confirmed in trans by family testing (PMID: 24052634). The variant has been reported to segregate with haematuria in heterozygous individuals from at least two families (PMID: 12325029, 30506145). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3, PP1. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 31, 2020	- -

Glomerulonephritis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Jan 08, 2021

- -

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 23, 2022

- -

Autosomal recessive Alport syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jan 27, 2017

- -

Benign familial hematuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 19, 2018

A heterozygous frameshift deletion variant, NM_000092.4(COL4A4):c.2638delG, has been identified in exon 30 of 48 of the COL4A4 gene. This deletion is predicted to create a frameshift starting at amino acid position 880, introducing a stop codon 70 residues downstream (NP_000083.3(COL4A4):p.(Ala880Hisfs*70)). This variant is predicted to result in loss of protein function through nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. However, truncation of the protein (including the loss of half the triple-helical region and both C4 domains) as a result of a NMD-escape mechanism has not been excluded. The variant is present in the gnomAD database at a frequency of 0.001% (3 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic in multiple patients, in either homozygous or compound heterozygous state, with Alport syndrome (ClinVar; Storey, H. et al., 2013; Dagher, H. et al., 2002). In addition, several different variants downstream, predicted to cause NMD, have also been reported pathogenic in patients with Alport Syndrome (ClinVar, HGMD). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

This sequence change creates a premature translational stop signal (p.Ala880Hisfs*70) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is present in population databases (rs778043831, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 12325029, 17216251, 24052634). This variant is also known as 2864delG. ClinVar contains an entry for this variant (Variation ID: 550471). For these reasons, this variant has been classified as Pathogenic. -

COL4A4-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2023

The COL4A4 c.2638delG variant is predicted to result in a frameshift and premature protein termination (p.Ala880Hisfs*70). This variant has been reported to be pathogenic for autosomal recessive Alport syndrome and autosomal dominant thin glomerular basement membrane disease (TBMD) (see for example, Dagher et al. 2002. PubMed ID: 12325029; Jayasinghe et al. 2020. PubMed ID: 32939031, Suppl. Table S2). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD. Frameshift variants in COL4A4 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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