rs104886132

Positions:

• chrX-108598705-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_033380.3(COL4A5):​c.1783G>A​(p.Gly595Arg) 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. Variant has been reported in Lovd as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23

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_pathogenic. Variant got 6 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, 5 uncertain in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771
• PP5: Variant X-108598705-G-A is Pathogenic according to our data. Variant chrX-108598705-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.1783G>A	p.Gly595Arg	missense_variant	25/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.1783G>A	p.Gly595Arg	missense_variant	25/53	1	NM_033380.3
COL4A5	ENST00000483338.1	c.607G>A	p.Gly203Arg	missense_variant	9/20	1
COL4A5	ENST00000361603.7	c.1783G>A	p.Gly595Arg	missense_variant	25/51	2		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	19
DANN	Benign	0.93
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	-0.042	T
MutationAssessor	Benign	0.26	N;N;.
MutationTaster	Benign	0.93	A;A
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.48	N;N;.
REVEL	Uncertain	0.61
Sift	Benign	0.66	T;T;.
Sift4G	Benign	0.52	T;T;.
Polyphen		0.94, 0.79	.;P;P
Vest4		0.72
MutPred		0.74		Gain of methylation at G595 (P = 0.021);Gain of methylation at G595 (P = 0.021);.;
MVP		0.92
MPC		0.36
ClinPred		0.58	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs104886132; hg19: chrX-107841935;