rs184730597

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000091.5(COL4A3):c.172G>A(p.Gly58Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,611,166 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: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:4

Conservation

PhyloP100: 4.93

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, 0.979

PP5

Variant 2-227240170-G-A is Pathogenic according to our data. Variant chr2-227240170-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553693.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=4, Pathogenic=1}. Variant chr2-227240170-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5 link	c.172G>A	p.Gly58Ser	missense_variant	Exon 3 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.172G>A	p.Gly58Ser	missense_variant	Exon 3 of 52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000247

AC:

AN:

243384

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132016

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000882

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:

0.0000181

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1458968

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

725390

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000900

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:2

Aug 11, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features of Alport syndrome. The majority of the pathogenic variants in this gene involve the substitution of a glycine residue in the triple-helix domain, resulting in disruption of protein function (PMID: 29632050, 21421911, 19344236). Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Mar 27, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the published literature in an individual with benign familial hematuria (PMID: 24854265); 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: 34426522, 34400539, 28632965, 24854265) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 58 of the COL4A3 protein (p.Gly58Ser). This variant is present in population databases (rs184730597, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of benign familial hematuria (PMID: 24854265). ClinVar contains an entry for this variant (Variation ID: 553693). 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. 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. -

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

Pathogenic:1

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome

Pathogenic:1

May 25, 2020

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_v1.1.1, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine (exon 3). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 (6 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0601 - Variant affects at least one well-established (essential) functional domain or motif (glycine residue of the Gly-X-Y motif in triple helical region; PDB). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as likely pathogenic and a variant of uncertain significance (ClinVar, PMIDs: 28632965, 24854265). It has been reported in a glomerular familial microscopic hematuria (FMH) patient cohort and a hematuric nephropathy patient cohort. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Autosomal dominant Alport syndrome

Pathogenic:1

Oct 21, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PP3, PP5 -

not specified

Uncertain:1

Jan 20, 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.172G>A (p.Gly58Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 243384 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.172G>A has been reported in the literature in at-least one individual affected with benign familial hematuria (example: Moriniere_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive Alport syndrome

Uncertain:1

Sep 12, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.6

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MVP

0.95

MPC

0.75

ClinPred

1.0

GERP RS

5.9

Varity_R

0.95

gMVP

0.93

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