rs868002181

chr2-227280970-G-Achr2-227280970-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000091.5(COL4A3):c.2452G>A(p.Gly818Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000735 in 1,414,456 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 6.43

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

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 2-227280970-G-A is Pathogenic according to our data. Variant chr2-227280970-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447169.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=4, Likely_pathogenic=1}. Variant chr2-227280970-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.2452G>A	p.Gly818Arg	missense_variant	31/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.329+734C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.2452G>A	p.Gly818Arg	missense_variant	31/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.329+734C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000114 AC: 2 AN: 174872 Hom.: 0 AF XY: 0.0000215 AC XY: 2 AN XY: 93174

Gnomad AFR exome AF: 0.00

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: 0.0000277

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000735 AC: 104 AN: 1414456 Hom.: 0 Cov.: 31 AF XY: 0.0000758 AC XY: 53 AN XY: 699032

Gnomad4 AFR exome AF: 0.0000311

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: 0.0000929

Gnomad4 OTH exome AF: 0.0000341

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2021	Reported as a single heterozygous variant in several unrelated individuals with features suggestive of Alport syndrome (Gast et al., 2016; Sen et al., 2017; Connaughton et al., 2019; Yao et al., 2019); of note, one individual inherited this variant from an unaffected parent; Reported with a pathogenic variant on the opposite allele (in trans) with a second COL4A3 variant in an individual with features suggestive of Alport syndrome (Storey et al., 2013); Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (Stenson et al., 2014; Jais et al., 2000); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28780565, 24077912, 10752524, 24052634, 30773290, 26346198, 30647093) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 25, 2016	- -
Likely pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 818 of the COL4A3 protein (p.Gly818Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Alport syndrome (PMID: 24052634, 26346198, 30586318, 30647093, 30773290; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447169). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL4A3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 27, 2022	- -

COL4A3-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 2022

The COL4A3 c.2452G>A variant is predicted to result in the amino acid substitution p.Gly818Arg. This variant was reported in the compound heterozygous state in an individual with Alport syndrome (Patient 11, Storey et al. 2013. PubMed ID: 24052634). This variant was also reported, along with another variant in COL4A3 (phase not noted) in siblings with likely Alport disease and likely hereditary nephritis (Family F2, Gast et al. 2016. PubMed ID: 26346198) and in an individual with glomerulopathy (Supplemental Table 7, Patient ID: CKD152, Groopman et al. 2019. PubMed ID: 30586318). This variant was also reported with a COL4A4 missense variant in an individual with Alport syndrome and both were maternally inherited (Supplemental Table 2, Patient 7, Sen et al. 2017. PubMed ID: 28780565). Of note, for that patient the variant was reported to track with disease in four affected and two unaffected individuals. This variant was also reported in the heterozygous state in an individual with hematuria (Family ID: B2347, Individual ID: 17, Connaughton et al. 2019. PubMed ID: 30773290) and in an individual with steroid-resistant nephrotic syndrome, undescended testes, and a penile anomaly (Supplemental Table 2, Patient 64, Sen et al. 2017. PubMed ID: 28780565). Of note the second patient listed also carried a de novo WT1 variant and the COL4A3 variant was inherited from an unaffected father. This variant was also reported in the heterozygous state in an individual with focal segmental glomerulosclerosis (FSGF) (Patient 7215, Family F23, Yao et al. 2019. PubMed ID: 30647093). This variant is reported in 0.0028% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-228145686-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance, to likely pathogenic, to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/447169/). The p.Gly818Arg residue is located in the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (UniProt residues 43-1438, Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK21582/). Taken together, this variant is interpreted as likely pathogenic. -

Autosomal dominant Alport syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Feb 14, 2019

- -

Autosomal recessive Alport syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 10, 2021

NM_000091.4(COL4A3):c.2452G>A(G818R) is a missense variant classified as a variant of uncertain significance in the context of COL4A3-related Alport syndrome. G818R has been observed in cases with relevant disease (PMID: 30773290, 28780565, 26346198, 24052634). Functional assessments of this variant are not available in the literature. G818R has been observed in population frequency databases (gnomAD: NFE 0.003%). In summary, there is insufficient evidence to classify NM_000091.4(COL4A3):c.2452G>A(G818R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.99		Gain of MoRF binding (P = 0.0118);
MVP		0.90
MPC		0.23
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs868002181; hg19: chr2-228145686;