rs982188184
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2
The NM_033380.3(COL4A5):c.4898C>T(p.Ala1633Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,209,553 control chromosomes in the GnomAD database, including 1 homozygotes. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000072 ( 1 hom., 1 hem., cov: 22)
Exomes 𝑓: 0.0000091 ( 0 hom. 4 hem. )
Consequence
COL4A5
NM_033380.3 missense
NM_033380.3 missense
Scores
6
5
6
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. 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. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM1
In a domain Collagen IV NC1 (size 224) in uniprot entity CO4A5_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_033380.3
PP3
MetaRNN computational evidence supports a deleterious effect, 0.776
BS2
High Hemizygotes in GnomAdExome4 at 4 XL gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000717 AC: 8AN: 111647Hom.: 1 Cov.: 22 AF XY: 0.0000296 AC XY: 1AN XY: 33813
GnomAD3 genomes
AF:
AC:
8
AN:
111647
Hom.:
Cov.:
22
AF XY:
AC XY:
1
AN XY:
33813
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000911 AC: 10AN: 1097906Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4AN XY: 363294
GnomAD4 exome
AF:
AC:
10
AN:
1097906
Hom.:
Cov.:
30
AF XY:
AC XY:
4
AN XY:
363294
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000717 AC: 8AN: 111647Hom.: 1 Cov.: 22 AF XY: 0.0000296 AC XY: 1AN XY: 33813
GnomAD4 genome
AF:
AC:
8
AN:
111647
Hom.:
Cov.:
22
AF XY:
AC XY:
1
AN XY:
33813
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2025 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1627 of the COL4A5 protein (p.Ala1627Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL4A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 591064). 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) indicates that this missense variant is not expected to disrupt COL4A5 protein function with a negative predictive value of 95%. 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. - |
X-linked Alport syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 03, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;T
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;L
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
0.55
.;P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at