rs772708743

Positions:

Variant summary

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

The NM_000091.5(COL4A3):c.898G>A(p.Gly300Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,461,620 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: not found (cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11U:2

Conservation

PhyloP100: 5.67

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 2-227256035-G-A is Pathogenic according to our data. Variant chr2-227256035-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227256035-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5 linkuse as main transcript	c.898G>A	p.Gly300Arg	missense_variant	16/52	ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1 linkuse as main transcript	n.1592+3143C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 linkuse as main transcript	c.898G>A	p.Gly300Arg	missense_variant	16/52	1	NM_000091.5	ENSP00000379823	P1	Q01955-1
MFF-DT	ENST00000439598.6 linkuse as main transcript	n.1592+3143C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249426

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135336

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 23, 2023	PP1, PP3, PM1, PS4_moderate -
Likely pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 300 of the COL4A3 protein (p.Gly300Arg). This variant is present in population databases (rs772708743, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant Alport syndrome (PMID: 25575550, 26809805; Invitae). ClinVar contains an entry for this variant (Variation ID: 562427). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant Alport syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 09, 2024	Criteria applied: PM1_STR,PS4_MOD,PM2_SUP,PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 17, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Oct 29, 2018	- -

Benign familial hematuria

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 22, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 1.00; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000562427). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Alport syndrome

Pathogenic:1Uncertain:1

Uncertain significance, flagged submission	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 21, 2021	The COL4A3 c.898G>A variant is classified as a LIKELY PATHOGENIC variant (PS4, PP3, PP4, PP5) This variant is a single nucleotide change from a guanine to an adenine at position 898 which is predicted to change the Glycine at position 300 in the protein to Arginine. The variant is in exon 16 and is located in collagen triple helix repeat protein domain of the COL4A3 gene. The variant has been reported in multiple individuals and families with Alport syndrome (PMID:2557550, 32647767). The prevalence of this variant in affected individuals is increasd compated with the prevalence in controls (PS4). The variant is in dbSNP (rs772708743) but is rare in population databases (gnomAD 5/249426, 0 homozygote). The variant has been reported in ClinVar (Variation ID: 562427) and HGMD (Accession No: CM151508) as Pathogenic/Likely pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). Patient's phenotype is highly specific for Alport syndrome with a single genetic etiology (PP4). -

COL4A3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 23, 2024

The COL4A3 c.898G>A variant is predicted to result in the amino acid substitution p.Gly300Arg. This variant has been reported in the heterozygous state in individuals with Alport syndrome (Mencarelli et al. 2015. PubMed ID: 25575550; Weber et al. 2016. PubMed ID: 26809805; Groopman et al. 2018. PubMed ID: 30586318. Table S7; Rao et al. 2019. PubMed ID: 31328266. Table S3). This variant has also been reported in individuals in a family with IgA nephropathy (Li et al. 2020. PubMed ID: 32647767). Furthermore, the p.Gly300Arg variant affects a Gly residue of the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (Mariyama et al. 1994. PubMed: 8083201; Savige et al. 2021. PubMed: 33854215; Gibson et al. 2022. PubMed: 35177655). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

not specified

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Feb 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

1.0

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.98

Loss of ubiquitination at K298 (P = 0.0435);

MVP

0.87

MPC

0.83

ClinPred

1.0

GERP RS

5.8

Varity_R

0.98

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: -9

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