chr2-227052367-G-C

Position:

chr2-227052367-G-C

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.Ser969Ter) 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:15

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/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5 linkuse as main transcript	c.2906C>G	p.Ser969Ter	stop_gained	32/48	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.2906C>G	p.Ser969Ter	stop_gained	32/48	5	NM_000092.5	ENSP00000379866	P1

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive Alport syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	May 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 18, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 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; This variant is associated with the following publications: (PMID: 34662886, 34758253, 29431110, 30406062, 25525159, 30647093, 31980526, 32723786, 35649421, 24052634, 26346198, 12325029, 36939041) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 31, 2023	- -

Alport syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Apr 03, 2018	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

COL4A4-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 26, 2022	PVS1, PS1_Supporting, PM2, PM3 -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 20, 2024	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. -

Chronic kidney disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Cavalleri Lab, Royal College of Surgeons in Ireland

May 28, 2020

PVS1, PS1 -

Benign familial hematuria

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genomics England Pilot Project, Genomics England

- -

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

MutationTaster

Benign

1.0

A;A

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