chr2-227293286-CCCTGGAAGT-C

Position:

• chr2-227293286-CCCTGGAAGT-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_000091.5(COL4A3):​c.3321_3329delAAGTCCTGG​(p.Ser1108_Gly1110del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000273 in 1,613,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: COL4A3 NM_000091.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:5
• Conservation: PhyloP100: 5.75

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]

MFF-DT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000091.5.
• PP5: Variant 2-227293286-CCCTGGAAGT-C is Pathogenic according to our data. Variant chr2-227293286-CCCTGGAAGT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553803.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=2, Likely_pathogenic=5}. Variant chr2-227293286-CCCTGGAAGT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.3321_3329delAAGTCCTGG	p.Ser1108_Gly1110del	disruptive_inframe_deletion	38/52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.3321_3329delAAGTCCTGG	p.Ser1108_Gly1110del	disruptive_inframe_deletion	38/52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000441 AC: 11 AN: 249378 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461460 Hom.: 0 AF XY: 0.0000289 AC XY: 21 AN XY: 727044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2024	In-frame deletion of 3 amino acids within the triple helical domain; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 15618242, 36013122, 36292665, 33233744, 12028435) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This variant, c.3321_3329del, results in the deletion of 3 amino acid(s) of the COL4A3 protein (p.Ser1108_Gly1110del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs756539994, gnomAD 0.01%). This variant has been observed in individuals with clinical features of Alport syndrome (PMID: 12028435; Invitae). This variant is also known as c.3321del9. ClinVar contains an entry for this variant (Variation ID: 553803). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Autosomal dominant Alport syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Aug 07, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jul 29, 2022	- -

Alport syndrome 3b, autosomal recessive Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 18, 2024	- -
Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

Autosomal recessive Alport syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 10, 2021	NM_000091.4(COL4A3):c.3321_3329del9(S1108_G1110del) is an in-frame deletion variant classified as a variant of uncertain significance in the context of COL4A3-related Alport syndrome. S1108_G1110del has been observed in a case with relevant disease (PMID: 33233744). Functional assessments of this variant are not available in the literature. S1108_G1110del has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, there is insufficient evidence to classify NM_000091.4(COL4A3):c.3321_3329del9(S1108_G1110del) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana	Nov 18, 2020	- -

COL4A3-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 05, 2023

The COL4A3 c.3321_3329del9 variant is predicted to result in an in-frame deletion (p.Ser1108_Gly1110del). This variant was reported in a female patient with microhematuria and proteinuria and other COL4A variants were not reported (Longo et al 2002. PubMed ID: 12028435).The c.3321_3329del9 variant was also reported with either COL4A4 or COL4A5 Gly substitution variants in three family members of a large family with proposed digenic inheritance for COL4A-related disorders (reported as c.3307_3315del in Zupan A et al 2020. PubMed ID: 33233744). At PreventionGenetics, we have observed the c.3321_3329del9 variant in the presence of a second COL4A3 variant in two patients with renal disorders (internal data). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD, indicating this variant may not be a primary cause of disease in the heterozygous state (http://gnomad.broadinstitute.org/variant/2-228158002-CCCTGGAAGT-C). This variant is interpreted as likely pathogenic for autosomal recessive COL4A3-related disorders. -

Alport syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 08, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Dominant negative and loss-of-function are known mechanisms of disease in this gene and are associated with Alport syndrome (MONDO:0018965), COL4A3-related. 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 hematuria MIM#141200) (OMIM). (I) 0216 - In-frame deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 12 heterozygotes, 0 homozygotes). (SP) 0601 - Variant is located in the well-established functional triple helical domain (DECIPHER). However, this in-frame deletion restores a G-X-Y repeat. (SP) 0705 - No comparable in-frame deletion or missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in three heterozygote individuals, one with Alport syndrome (PMID: 12028435), one with bilateral hearing loss and congenital hypothyroidism (PMID: 34178707) and one with haematuria and proteinuria (VCGS internal database). It has also been classified as likely pathogenic or pathogenic by diagnostic laboratories in ClinVar, as well as VUS classifications. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 07, 2023

Variant summary: COL4A3 c.3321_3329delAAGTCCTGG (p.Ser1108_Gly1110del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 4.4e-05 in 249378 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (4.4e-05 vs 0.0019), allowing no conclusion about variant significance. c.3321_3329delAAGTCCTGG has been reported in the literature as a non-informative genotype in individuals affected with microhematuria, proteinuria and other renal manifestations (example, Longo_2002, Frasca_2005, Zupan_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15618242, 36013122, 36292665, 12028435, 33233744). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (pathogenic/likely pathogenic, n=5; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2024

The c.3321_3329delAAGTCCTGG (p.S1108_G1110del) alteration is located in exon 38 (coding exon 38) of the COL4A3 gene. This alteration consists of an in-frame deletion of 9 nucleotides between nucleotide positions c.3321 and c.3329, resulting in the deletion of 3 residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs756539994; hg19: chr2-228158002;