rs982188184

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

Scores

6
5
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.91
Variant links:
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

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A5NM_033380.3 linkc.4898C>T p.Ala1633Val missense_variant Exon 52 of 53 ENST00000328300.11 NP_203699.1 P29400-2Q49AM6A7MBN3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A5ENST00000328300.11 linkc.4898C>T p.Ala1633Val missense_variant Exon 52 of 53 1 NM_033380.3 ENSP00000331902.7 P29400-2

Frequencies

GnomAD3 genomes
AF:
0.0000717
AC:
8
AN:
111647
Hom.:
1
Cov.:
22
AF XY:
0.0000296
AC XY:
1
AN XY:
33813
show subpopulations
Gnomad AFR
AF:
0.0000977
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000287
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:
0.0000188
Gnomad OTH
AF:
0.000665
GnomAD4 exome
AF:
0.00000911
AC:
10
AN:
1097906
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
4
AN XY:
363294
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000852
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:
0.00000119
Gnomad4 OTH exome
AF:
0.000130
GnomAD4 genome
AF:
0.0000717
AC:
8
AN:
111647
Hom.:
1
Cov.:
22
AF XY:
0.0000296
AC XY:
1
AN XY:
33813
show subpopulations
Gnomad4 AFR
AF:
0.0000977
Gnomad4 AMR
AF:
0.000287
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.000665
Alfa
AF:
0.000142
Hom.:
1
Bravo
AF:
0.000125

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 providedresearchGharavi Laboratory, Columbia UniversitySep 16, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 08, 2025This 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 03, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
.;T
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Uncertain
0.53
D
MutationAssessor
Benign
1.3
.;L
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.4
N;N
REVEL
Pathogenic
0.78
Sift
Benign
0.18
T;T
Sift4G
Benign
0.16
T;T
Polyphen
0.55
.;P
Vest4
0.58
MVP
0.94
MPC
0.86
ClinPred
0.96
D
GERP RS
5.4
Varity_R
0.59
gMVP
0.90

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: rs982188184; hg19: chrX-107938573; API