rs181528936

Variant summary

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

The NM_000092.5(COL4A4):​c.1441G>A​(p.Gly481Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,613,568 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 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

10
8
1

Clinical Significance

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

Conservation

PhyloP100: 4.18
Variant links:
Genes affected
COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

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, 0.94
PP5
Variant 2-227089886-C-T is Pathogenic according to our data. Variant chr2-227089886-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 585525.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=2, Likely_pathogenic=1}. Variant chr2-227089886-C-T is described in Lovd as [Pathogenic]. Variant chr2-227089886-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A4NM_000092.5 linkc.1441G>A p.Gly481Ser missense_variant Exon 21 of 48 ENST00000396625.5 NP_000083.3 P53420

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A4ENST00000396625.5 linkc.1441G>A p.Gly481Ser missense_variant Exon 21 of 48 5 NM_000092.5 ENSP00000379866.3 P53420

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151990
Hom.:
0
Cov.:
31
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000842
AC:
21
AN:
249452
Hom.:
0
AF XY:
0.0000813
AC XY:
11
AN XY:
135336
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000609
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461460
Hom.:
0
Cov.:
32
AF XY:
0.0000193
AC XY:
14
AN XY:
727064
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000559
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152108
Hom.:
0
Cov.:
31
AF XY:
0.0000134
AC XY:
1
AN XY:
74352
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000896
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000745
AC:
9

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2Uncertain:3
Nov 30, 2022
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
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 481 of the COL4A4 protein (p.Gly481Ser). This variant is present in population databases (rs181528936, gnomAD 0.06%). This missense change has been observed in individuals with clinical features of Alport syndrome and/or hematuria (PMID: 15618242; internal data). ClinVar contains an entry for this variant (Variation ID: 585525). Invitae Evidence 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 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 COL4A4 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jul 20, 2021
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3, PM1, PM2 -

Jun 13, 2019
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -

May 09, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A4 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: 15618242, 34400539) -

Autosomal recessive Alport syndrome;CN376803:Hematuria, benign familial, 1 Pathogenic:1
May 14, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

COL4A4-related disorder Pathogenic:1
Mar 15, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The COL4A4 c.1441G>A variant is predicted to result in the amino acid substitution p.Gly481Ser. This variant is reported in 0.061% of alleles in individuals of Latino descent in gnomAD. This variant affects a glycine (Gly) residue of the conserved triple helical domain (residues 65 – 1459) of the COL4A4 protein (uniprot.org), where substitutions of the glycine (Gly) residue are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has been reported in an individual with an episode of macroscopic hematuria alongside persistent microhematuria and her affected mother (Frasca et al. 2005. PubMed ID: 15618242). In addition, at other glycine (Gly) residues within this domain, substitutions of a glycine (Gly) with a serine (Ser) have been widely reported to be pathogenic for autosomal recessive or dominant COL4A4 nephropathy (see for example, p.Gly1242Ser in Zhang et al. 2021. PubMed ID: 33772369, autosomal recessive Alport syndrome; p.Gly1201Ser in Fig. 4a of Mochizuki et al. 1994. PubMed ID: 7987396, autosomal recessive Alport syndrome; p.Gly748Ser in Papazachariou et al. 2017. PubMed ID: 28632965, autosomal dominant familial microscopic hematuria). Taken together, this variant is interpreted as pathogenic for both autosomal recessive and dominant COL4A4 nephropathy. -

not specified Uncertain:1
Sep 10, 2024
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: COL4A4 c.1441G>A (p.Gly481Ser) results in a non-conservative amino acid change in 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 8.4e-05 in 249452 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in COL4A4 causing Alport Syndrome, Autosomal Recessive (8.4e-05 vs 0.0011), allowing no conclusion about variant significance. c.1441G>A has been reported in the literature in at least one individual affected with macroscopic haematuria with microhaematuria (Frasc_2004). The report does not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15618242, 36699462, 36292665). ClinVar contains an entry for this variant (Variation ID: 585525). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.93
D
M_CAP
Pathogenic
0.47
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.7
M
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-5.5
D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0050
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.96
MVP
0.90
MPC
0.58
ClinPred
0.90
D
GERP RS
5.6
Varity_R
0.46
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.

Other links and lift over

dbSNP: rs181528936; hg19: chr2-227954602; API