rs200672668

Positions:

chr2-227273108-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000091.5(COL4A3):c.1918G>A(p.Gly640Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,642 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.17

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:):

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

PP5

Variant 2-227273108-G-A is Pathogenic according to our data. Variant chr2-227273108-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227273108-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-227273108-G-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.1918G>A	p.Gly640Arg	missense_variant	26/52	ENST00000396578.8	NP_000082.2	Q01955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 linkuse as main transcript	c.1918G>A	p.Gly640Arg	missense_variant	26/52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000163

AC:

AN:

245844

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

133802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00000910

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461392

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2021	Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene; 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: 11134255, 24633401, 24052634, 29854973) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 640 of the COL4A3 protein (p.Gly640Arg). This variant is present in population databases (rs200672668, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal dominant and autosomal recessive Alport syndrome (PMID: 11134255, 24052634, 29854973; 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: 371669). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 protein function. For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant Alport syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 07, 2024	Criteria applied: PM1_STR,PS4_MOD,PM2_SUP,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	Sep 05, 2024	Combined evidence strength is Very Strong (score = 8).Very Strong: ClinVar classifies this variant as Pathogenic, 2 stars (reviewed Feb '24, 6 submissions of which 2 are from high confidence submitters) (PP5). Equivalent variant chr2:227273108 G⇒C (Gly640Arg) is classified Pathogenic by UniProt Variants (confirmed using the germline classifier) (PS1). MetaRNN = 0.952 is greater than 0.939 ⇒ strong pathogenic (PP3). Hot-spot of length 17 amino-acids has 9 missense/in-frame variants (5 pathogenic variants, 4 uncertain variants and no benign), which qualifies as moderate pathogenic.UniProt protein CO4A3_HUMAN region of interest 'Disordered' has 471 missense/in-frame variants (184 pathogenic variants, 263 uncertain variants and 24 benign variants), which qualifies as moderate pathogenic.UniProt protein CO4A3_HUMAN region of interest 'Triple-helical region' has 720 missense/in-frame variants (270 pathogenic variants, 408 uncertain variants and 42 benign variants), which qualifies as moderate pathogenic (PM1). GnomAD genomes homozygous allele count = 0 is less than 2 for AD/AR gene COL4A3, good gnomAD genomes coverage = 31.0.GnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene COL4A3, good gnomAD exomes coverage = 37.5 (PM2). We observed this variant in a 50-year-old man patient with Alport Syndrome 3A. -

Autosomal recessive Alport syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Nov 10, 2016

- -

Microscopic hematuria

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Nov 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.1

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.80

Vest4

0.97

MutPred

0.99

Gain of methylation at G640 (P = 0.0131);

MVP

0.84

MPC

0.23

ClinPred

0.99

GERP RS

4.0

Varity_R

0.94

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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