2-227164755-AGGTGCTCCTGCTGCCGCTCCTGCT-A

Position:

chr2-227164755-AGGTGCTCCTGCTGCCGCTCCTGCT-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000396578.8(COL4A3):c.40_63del(p.Leu14_Leu21del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000557 in 1,525,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q10Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

COL4A3
ENST00000396578.8 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.454

Variant links:

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. 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. [provided by RefSeq, Jun 2010]

COL4A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-227164755-AGGTGCTCCTGCTGCCGCTCCTGCT-A is Pathogenic according to our data. Variant chr2-227164755-AGGTGCTCCTGCTGCCGCTCCTGCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 192299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227164755-AGGTGCTCCTGCTGCCGCTCCTGCT-A is described in Lovd as [Pathogenic]. Variant chr2-227164755-AGGTGCTCCTGCTGCCGCTCCTGCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5 linkuse as main transcript	c.40_63del	p.Leu14_Leu21del	inframe_deletion	1/52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 linkuse as main transcript	c.40_63del	p.Leu14_Leu21del	inframe_deletion	1/52	1	NM_000091.5	ENSP00000379823	P1	Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000577

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:

0.000140

AC:

AN:

121044

Hom.:

AF XY:

0.000165

AC XY:

AN XY:

66524

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000125

Gnomad ASJ exome

AF:

0.00128

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000671

Gnomad OTH exome

AF:

0.000263

GnomAD4 exome

AF:

0.0000597

AC:

AN:

1373804

Hom.:

AF XY:

0.0000694

AC XY:

AN XY:

677680

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000141

Gnomad4 ASJ exome

AF:

0.00129

Gnomad4 EAS exome

AF:

0.0000288

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.000262

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151956

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000577

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

Alfa

AF:

0.000305

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive Alport syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	This inframe deletion in the non-repeat region can change the length of the protein and disrupt protein function (PM4_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 28570636, 23927549, 22887978, PM3_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 28570636, PS3_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000192299).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000140, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2019	Variant summary: COL4A3 c.40_63del24 (p.Leu14_Leu21del) results in an in-frame deletion that is predicted to remove eight amino acids from the COL4A3 signal peptide sequence of the encoded protein. The variant allele was found at a frequency of 0.00022 in 125078 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in COL4A3 causing autosomal recessive Alport Syndrome (0.00022 vs 0.002), allowing no conclusion about variant significance. c.40_63del24 has been reported in the literature in multiple individuals affected with autosomal recessive Alport Syndrome worldwide (Zhang_2012, Oka_2014, Webb_2014, Chiereghin_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a disruption of COL4A3 signal peptide, possibly altering protein secretion (Chiereghin_2017). No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with COL4A3-related nephropathy. Glycine changes that are part of a G-X-Y repeat in the triple helix of a collagen domain are known to have a dominant negative effect (PMID: 12028435). (I) 0108 - This gene is associated with both recessive (Alport syndrome 2 MIM#203780) and dominant disease (Alport syndrome 3 MIM#104200 and benign familial haematuria MIM#141200) (OMIM). (I) 0216 - In-frame insertion/deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (17 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative, smaller inframe deletion in the same region has been observed in gnomAD (v3) (208 heterozygotes, 0 homozygotes). (I) 0601 - Variant is located in the well-established functional signal peptide. This variant results in the deletion of eight amino acids, resulting in protein mislocalization (PMID: 28570636). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and observed in mostly homozygous and compound heterozygous individuals with Alport syndrome, or hearing loss with proteinuria and occular anomalies. Heterozygous individuals may not be clinically affected, or present with microhaematuria (ClinVar, PMID: 28570636, PMID: 23927549). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2023	This variant, c.40_63del, results in the deletion of 8 amino acid(s) of the COL4A3 protein (p.Leu14_Leu21del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs774798108, gnomAD 0.1%). This variant has been observed in individuals with Alport syndrome (PMID: 23927549, 28570636). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 192299). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects COL4A3 function (PMID: 28570636). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2022	Published with a carrier frequency within the Ashkenazi Jewish population of 1 in 183, and may be a founder variant for Alport syndrome in this population (Webb et al., 2014); Published in vitro studies demonstrate that the deletion alters the COL4A3 signal peptide and changes the subcellular protein localization; variant results in diffuse localization in the cytoplasm and nucleus (Chiereghin et al., 2017); In-frame deletion of 8 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 33772369, 12028435, 14582039, 22887978, 23927549, 28570636, 24633401, 29801666) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2024

The c.40_63del24 (p.L14_L21del) alteration, located in coding exon 1 of the COL4A3 gene, results from an in-frame deletion of 24 nucleotides at positions c.40 to c.63. This results in the deletion of 8 residues from codons p.14 to p.21. Based on data from gnomAD, the c.40_63del24 allele has an overall frequency of 0.014% (17/121044) total alleles studied. The highest observed frequency was 0.13% (10/7802) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state or in conjunction with other COL4A3 variants in individuals with features consistent with COL4A3-related Alport syndrome; in at least one instance, the variants were identified in trans (Zhang, 2012; Oka, 2014; Chiereghin, 2017). It has also been observed to segregate with disease in an affected family (Webb, 2014). The deleted amino acid positions are not well conserved in available vertebrate species. In an assay testing COL4A3 function, this variant showed a functionally abnormal result (Chiereghin, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

COL4A3-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 10, 2023

The COL4A3 c.40_63del24 variant is predicted to result in an in-frame deletion (p.Leu14_Leu21del). This variant has been reported to be pathogenic for Alport syndrome (AS) (in the homozygous state), and microhematuria/mild proteinuria (in the heterozygous state) (Webb et al. 2014. PubMed ID: 23927549; Longo et al. 2002. PubMed ID: 12028435; Chiereghin et al. 2017. PubMed ID: 28570636). In particular, this deletion was reported to be a pathogenic founder variant in the Ashkenazi Jewish population. This variant is reported in 0.13% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-228029471-AGGTGCTCCTGCTGCCGCTCCTGCT-A). This variant is interpreted as pathogenic. -

Alport syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

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