2-227248443-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000091.5(COL4A3):​c.469G>C​(p.Gly157Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000561 in 1,603,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

COL4A3
NM_000091.5 missense, splice_region

Scores

12
5
2
Splicing: ADA: 0.9999
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 5.18
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]
MFF-DT (HGNC:41067): (MFF divergent transcript)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A3NM_000091.5 linkc.469G>C p.Gly157Arg missense_variant, splice_region_variant Exon 9 of 52 ENST00000396578.8 NP_000082.2 Q01955-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A3ENST00000396578.8 linkc.469G>C p.Gly157Arg missense_variant, splice_region_variant Exon 9 of 52 1 NM_000091.5 ENSP00000379823.3 Q01955-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152052
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
249350
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135312
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.00000551
AC:
8
AN:
1451622
Hom.:
0
Cov.:
27
AF XY:
0.0000111
AC XY:
8
AN XY:
722778
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000505
Gnomad4 SAS exome
AF:
0.0000349
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000181
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152052
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:2
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

COL4A3: PM1:Strong, PM2, PS4:Supporting -

Mar 20, 2022
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 arginine, which is basic and polar, at codon 157 of the COL4A3 protein (p.Gly157Arg). This variant is present in population databases (rs764451365, gnomAD 0.006%). This missense change has been observed in individual(s) with bilateral sensorineural hearing loss (PMID: 23967202). ClinVar contains an entry for this variant (Variation ID: 550529). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Nov 09, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive Alport syndrome Uncertain:1
Jan 27, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Alport syndrome Uncertain:1
Jul 17, 2023
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with COL4A3-related nephropathy. Glycine changes that are part of a G-X-Y repeat in the triple helix of a collagen domain are known to have a dominant negative effect (PMID: 12028435). (I) 0108 - This gene is associated with both recessive (Alport syndrome 2 MIM#203780) and dominant disease (Alport syndrome 3 MIM#104200 and benign familial haematuria MIM#141200) (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated collagen domain and affects a glycine residue (DECIPHER). However this glycine residue is at a gap in the Gly-X-Y repeat motif. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as a VUS by four clinical laboratories in ClinVar, and in a paper where it was observed in an individual with thin basement membrane nephropathy who also had a likely pathogenic COL4A4 variant (PMID: 36292665). This variant has also been classified as likely pathogenic in the literature, where it was observed in an individual with autosomal recessive Alport syndrome (PMID: 33772369). Another literature report describes this variant as heterozygous in an individual with deafness who was not noted to have a second hit; the variant was not classified in this instance (PMID: 23967202). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome Uncertain:1
May 20, 2022
Fulgent Genetics, Fulgent Genetics
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
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.68
D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.81
T
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.6
H
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-6.8
D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.90
Loss of ubiquitination at K153 (P = 0.0498);
MVP
0.90
MPC
0.83
ClinPred
0.99
D
GERP RS
5.8
Varity_R
0.95
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
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.

Other links and lift over

dbSNP: rs764451365; hg19: chr2-228113159; API