rs121912861

Variant names:

• chr2-227022135-G-A
• rs121912861
• NM_000092.5:c.4129C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-227022135-G-A
• chr2-227022135-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 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:14
• Conservation: PhyloP100: 0.211
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive Alport syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
• Alport syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• autosomal dominant Alport syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-227022135-G-A is Pathogenic according to our data. Variant chr2-227022135-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.4129C>T	p.Arg1377*	stop_gained	Exon 44 of 48	ENST00000396625.5	NP_000083.3

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 248918 AF XY: 0.00000740

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000184 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Oct 22, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jun 03, 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.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. -

Nov 21, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Autosomal recessive Alport syndrome Pathogenic:3

Nov 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 16, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 20, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017407 /PMID: 9792860). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Alport syndrome Pathogenic:2

Feb 22, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 24, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Autosomal recessive Alport syndrome;CN376803:Hematuria, benign familial, 1 Pathogenic:1

Jan 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign familial hematuria Pathogenic:1

Jun 28, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant Alport syndrome Pathogenic:1

Jan 03, 2019

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

COL4A4-related disorder Pathogenic:1

Dec 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.21
Vest4		0.85
GERP RS		2.2
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912861; hg19: chr2-227886851;