rs772708743
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_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
NM_000091.5 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 5.67
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000091.5
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 | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.898G>A | p.Gly300Arg | missense_variant | 16/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.1592+3143C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.898G>A | p.Gly300Arg | missense_variant | 16/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.1592+3143C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249426Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135336
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461620Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727112
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
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 | Invitae | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 23, 2023 | PP1, PP3, PM1, PS4_moderate - |
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. - |
Autosomal dominant Alport syndrome Pathogenic:2
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 | - - |
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, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 19, 2023 | 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 (http://gnomad.broadinstitute.org/variant/2-228120751-G-A). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of ubiquitination at K298 (P = 0.0435);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -9
Find out detailed SpliceAI scores and Pangolin per-transcript scores at