NM_000091.5:c.3321_3329delAAGTCCTGG

Variant names:

• chr2-227293286-CCCTGGAAGT-C
• rs756539994
• NM_000091.5:c.3321_3329delAAGTCCTGG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 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). Synonymous variant affecting the same amino acid position (i.e. G1107G) has been classified as Likely benign.

• 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:9 U:5
• Conservation: PhyloP100: 5.75
• Publications: 2 publications found

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:41067): (MFF divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000091.5
• 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 submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.3321_3329delAAGTCCTGG	p.Ser1108_Gly1110del	disruptive_inframe_deletion	Exon 38 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.3321_3329delAAGTCCTGG	p.Ser1108_Gly1110del	disruptive_inframe_deletion	Exon 38 of 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

GnomAD2 exomes AF: 0.0000441 AC: 11 AN: 249378 AF XY: 0.0000369

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000179 AC: 8 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5488

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111978

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

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

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.000131 AC: 2 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Mar 28, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

May 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 07, 2019

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 29, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive Alport syndrome Pathogenic:1 Uncertain:1

Nov 18, 2020

Laboratory for Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

COL4A3-related disorder Pathogenic:1

Oct 05, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hematuria, benign familial, 2;C5882663:Autosomal dominant Alport syndrome;C5882699:Alport syndrome 3b, autosomal recessive Pathogenic:1

Mar 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome Pathogenic:1

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely 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 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

Dec 07, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=42/158	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs756539994; hg19: chr2-228158002;