rs1012489715

chrX-108668501-C-AchrX-108668501-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_033380.3(COL4A5):c.3787C>A(p.Pro1263Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1263S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.954

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 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.3787C>A	p.Pro1263Thr	missense_variant	41/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.3787C>A	p.Pro1263Thr	missense_variant	41/53	1	NM_033380.3
COL4A5	ENST00000361603.7	c.3787C>A	p.Pro1263Thr	missense_variant	41/51	2		P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	21
Dann	Uncertain	0.98
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.024	D;T
Polyphen		0.14	.;B
Vest4		0.57
MutPred		0.47		Gain of phosphorylation at P1263 (P = 0.0026);Gain of phosphorylation at P1263 (P = 0.0026);
MVP		0.90
MPC		0.33
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.53
gMVP		0.35

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: rs1012489715; hg19: chrX-107911731;