2-227289222-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000091.5(COL4A3):c.2954G>T(p.Gly985Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,548 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: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 5.70

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:

MFF-DT (HGNC:41067): (MFF divergent transcript)

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.993

PP5

Variant 2-227289222-G-T is Pathogenic according to our data. Variant chr2-227289222-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17490.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr2-227289222-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5 link	c.2954G>T	p.Gly985Val	missense_variant	Exon 35 of 52	ENST00000396578.8	NP_000082.2	Q01955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 link	c.2954G>T	p.Gly985Val	missense_variant	Exon 35 of 52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

248976

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135088

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000895

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 985 of the COL4A3 protein (p.Gly985Val). This variant is present in population databases (rs121912827, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 11961012, 25307543). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17490). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL4A3 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Apr 19, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene; This variant is associated with the following publications: (PMID: 11961012, 33838161) -

Autosomal recessive Alport syndrome

Pathogenic:1

May 23, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign familial hematuria

Pathogenic:1

May 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Alport syndrome

Uncertain:1

Apr 07, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.56

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.68

D;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.4

H;.

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

1.0

Gain of ubiquitination at K984 (P = 0.0964);.;

MVP

0.97

MPC

0.24

ClinPred

1.0

GERP RS

5.9

Varity_R

0.99

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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