rs35138315

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000092.5(COL4A4):c.2906C>G(p.Ser969*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,613,292 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S969S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

COL4A4
NM_000092.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 0.934

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 2-227052367-G-C is Pathogenic according to our data. Variant chr2-227052367-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 449549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227052367-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.2906C>G	p.Ser969*	stop_gained	Exon 32 of 48	ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.2906C>G	p.Ser969*	stop_gained	Exon 32 of 48	5	NM_000092.5	ENSP00000379866.3		P53420

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000681

AC:

AN:

249564

Hom.:

AF XY:

0.0000739

AC XY:

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.0000646

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:

0.000132

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000346

AC:

505

AN:

1461166

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

246

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

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:

0.000447

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000105

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000145

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive Alport syndrome

Pathogenic:7

Mar 21, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>G) at coding position 2906 of the COL4A4 gene that generates an early termition codon at Ser969 of the COL4A4 protein. As this variant occurs in exon 32 of 48, it is expected to result in loss of COL4A expression through expression of a truncated protein product or nonsense-mediated decay. This is a previously reported variant (ClinVar) that has been observed in the literature in several individuals with Alport Syndrome (PMID: 24052634) and focal segmental glomerulosclerosis (PMID: 26346198). This variant is present in the gnomAD population database (8 of 280956 alleles or 0.0064%). Because haploinsufficiency is a known mechanism of disease for COL4A4, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP5, PVS1 -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL4A4 c.2906C>G (p.Ser969X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Alport Syndrome in HGMD. The variant allele was found at a frequency of 6.8e-05 in 249564 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A4 causing Alport Syndrome, Autosomal Recessive (6.8e-05 vs 0.0016), allowing no conclusion about variant significance. c.2906C>G has been reported in the literature in multiple individuals affected with Alport Syndrome, Autosomal Recessive (Dagher_2002, Storey_2013, etc). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 18, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature termination codon at position 969 in exon 32 (of 48) of COL4A4 (p.Ser969*). It is expected to result in an absent or disrupted protein product in a gene where loss of function is a well-established mechanism of disease (PVS1). The variant is present in a large population cohort at a frequency of 0.006%, which is consistent with a recessive condition (rs35138315, 18/280956 alleles, 0 homozygotes in gnomAD v2.1.1 - PM2_Supporting). Furthermore, it has been reported as homozygous and compound heterozygous with a second pathogenic allele in multiple cases with Alport syndrome (PMID: 24052634 - PM3_Strong). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2_Supporting. -

Dec 18, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

May 27, 2020

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:3

May 31, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 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; This variant is associated with the following publications: (PMID: 34662886, 34758253, 29431110, 30406062, 25525159, 30647093, 31980526, 32723786, 35649421, 24052634, 26346198, 12325029, 36939041) -

Oct 07, 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.Ser969*) 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 (rs35138315, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Alport syndrome (PMID: 12325029, 24052634). ClinVar contains an entry for this variant (Variation ID: 449549). For these reasons, this variant has been classified as Pathogenic. -

Alport syndrome

Pathogenic:3

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with Alport syndrome. Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMIDs: 12028435; 24046192). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported (PMID: 28704582). Thin basement membrane nephropathy (TBMN) and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMIDs: 16467446, 17942953). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 (18 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are multiple pathogenic NMD-predicted variants in COL4A4 (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in homozygous or compound heterozygous state in multiple individuals with Alport syndrome. It has also been reported in heterozygous state in individuals with TBMN and FSGS (PMIDs: 12631110, 24052634, 26346198). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 03, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is heterozygous for a pathogenic variant c.2906C>G in the COL4A4 gene. This variant creates a premature stop codon p.(Ser969*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been widely reported in patients with autosomal recessive Alport syndrome (Storey et al 2013 J Am Soc Nephrol 24: 1945-1954), and some patients with thin basement membrane nephropathy (Buzza et al 2003 Kidney Int 63:447-453). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a low allele frequency of 0.006% (18/ 277, 194 alleles). This variant is considered to be pathogenic according to the ACMG guidelines. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

COL4A4-related disorder

Pathogenic:2

Aug 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL4A4 c.2906C>G variant is predicted to result in premature protein termination (p.Ser969*). This variant has been reported to be pathogenic for autosomal recessive Alport syndrome (see for example, Dagher et al. 2002. PubMed ID: 12325029; Storey et al. 2013. PubMed ID: 24052634; Gast et al. 2015. PubMed ID: 26346198). In addition, this variant in the heterozygous (carrier) state has been reported in an individual with recurrent and persistent hematuria (Barton et al. 2022. PubMed ID: 35649421). This variant is reported in 0.012% of alleles in individuals of European (non-Finnish) descent in gnomAD. Nonsense variants in COL4A4 are expected to be pathogenic. This variant is interpreted as pathogenic for both autosomal dominant and autosomal recessive COL4A4-related conditions. -

May 26, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS1_Supporting, PM2, PM3 -

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

Pathogenic:1

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Chronic kidney disease

Pathogenic:1

May 28, 2020

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1, PS1 -

Benign familial hematuria

Pathogenic:1

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.29

Eigen_PC

Benign

-0.040

FATHMM_MKL

Benign

0.18

Vest4

0.47

GERP RS

1.8

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