rs121912861

Positions:

• chr2-227022135-G-A

Variant summary

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

The NM_000092.5(COL4A4):​c.4129C>T​(p.Arg1377*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: COL4A4 NM_000092.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.211

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 (HGNC:):

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 2-227022135-G-A is Pathogenic according to our data. Variant chr2-227022135-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227022135-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.4129C>T	p.Arg1377*	stop_gained	44/48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.4129C>T	p.Arg1377*	stop_gained	44/48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 248918 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461862 Hom.: 0 Cov.: 37 AF XY: 0.0000124 AC XY: 9 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000324 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2024	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; Identified in a patient with thin basement membrane disease in published literature; variant reported to segregate with additional family members with hematuria but data is limited (PMID: 12631110); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37097554, 25525159, 31589614, 33712733, 31576025, 30586318, 32939031, 29854973, 38978054, 9792860, 12631110) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Arg1377*) 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 (rs121912861, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Alport syndrome and/or thin basement membrane disease with hematuria (PMID: 9792860, 12631110). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17407). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Autosomal recessive Alport syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 16, 2021	NM_000092.4(COL4A4):c.4129C>T(R1377*) is a nonsense variant classified as pathogenic in the context of COL4A4-related Alport syndrome. R1377* has been observed in cases with relevant disease (PMID: 9792860). Functional assessments of this variant are not available in the literature. R1377* has been observed in population frequency databases (gnomAD: ASJ 0.01%). In summary, NM_000092.4(COL4A4):c.4129C>T(R1377*) is a nonsense variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening. -

Alport syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Oct 24, 2018	This patient is heterozygous for a known pathogenic variant, c.4139C>T p.(Arg1377*), in the COL4A4 gene. This variant (dbSNP: rs121912861) creates a premature stop codon p.(Arg1377*), and may result in a null allele due to nonsense-mediated mRNA decay. This variant is considered to be pathogenic, and has been previously reported in conjunction with a second pathogenic mutation in two patients with Alport syndrome in the literature (Boye et al 1998 Am. J. Hum. Genet. 63:1329-40). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 22, 2020	- -

Benign familial hematuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 28, 2018

A heterozygous nonsense variant, NM_000092.4(COL4A4):c.4129C>T, has been identified in exon 44 of 48 of the COL4A4 gene. The variant is predicted to result in a premature stop codon at position 1377 of the protein, NP_000083.3(COL4A4):p.(Arg1377*). This variant is predicted to result in loss of protein function either through truncation (including loss of a quarter of the protein) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.00081% (2 heterozygotes, 0 homozygote). The variant has previously been described as pathogenic in multiple patients with Alport syndrome (ClinVar, Boye, E., et al. (1998), Buzza, M., et al. (2001), Buzza, M., et al. (2003)) and has also been shown to segregate with haematuria in these families. In addition, other truncating variants upstream and downstream of this variant have been reported as pathogenic in individuals with Alport sydrome. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

Kidney damage Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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Autosomal dominant Alport syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Jan 03, 2019

- -

COL4A4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2022

The COL4A4 c.4129C>T variant is predicted to result in premature protein termination (p.Arg1377*). This variant has been reported in the compound heterozygous or homozygous state in individuals with autosomal recessive Alport syndrome (Family AR18 in Boye et al 1998. PubMed ID: 9792860; Jayasinghe K et al 2020. PubMed ID: 32939031; Gillion V et al. 2018. PubMed ID: 29854973). This variant in the heterozygous state or compound heterozygous state has also been reported in individuals with hematuria (Buzza et al. 2003. PubMed ID: 12631110; Schrezenmeier et al. 2021. PubMed ID: 33712733; Zhang et al. 2020. PubMed ID: 31576025). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-227886851-G-A). Nonsense 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.19	N
Vest4		0.85
GERP RS		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121912861; hg19: chr2-227886851;