rs281874682

Positions:

• chrX-108598805-C-A
• chrX-108598805-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_033380.3(COL4A5):​c.1883C>A​(p.Pro628Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a compositionally_biased_region Pro residues (size 22) in uniprot entity CO4A5_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1883C>A	p.Pro628Gln	missense_variant	25/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1883C>A	p.Pro628Gln	missense_variant	25/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.707C>A	p.Pro236Gln	missense_variant	9/20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.1883C>A	p.Pro628Gln	missense_variant	25/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183089 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67619

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

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 Cov.: 30

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.54	.;D;T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	0.040	D
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;D;.
REVEL	Benign	0.27
Sift	Benign	0.22	T;T;.
Sift4G	Benign	0.30	T;T;.
Polyphen		0.10, 0.051	.;B;B
Vest4		0.38
MutPred		0.35		Loss of glycosylation at P628 (P = 0.0508);Loss of glycosylation at P628 (P = 0.0508);.;
MVP		0.68
MPC		0.28
ClinPred		0.31	T
GERP RS		5.9
Varity_R		0.33
gMVP		0.40

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: rs281874682; hg19: chrX-107842035;