rs982188184

Variant names:

• chrX-108695343-C-T
• rs982188184
• NM_033380.3:c.4898C>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP3 BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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]

ACMG classification

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
COL4A5	NM_033380.3	c.4898C>T	p.Ala1633Val	missense_variant	Exon 52 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.4898C>T	p.Ala1633Val	missense_variant	Exon 52 of 53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes AF: 0.0000717 AC: 8 AN: 111647 Hom.: 1 Cov.: 22 AF XY: 0.0000296 AC XY: 1 AN XY: 33813

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

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

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

Submissions by phenotype

not provided Uncertain:2

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

X-linked Alport syndrome Uncertain:1

Jan 03, 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	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

Other links and lift over

dbSNP: rs982188184; hg19: chrX-107938573;