rs104886131

Positions:

• chrX-108598702-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_033380.3(COL4A5):​c.1780G>A​(p.Gly594Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in Lovd as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense, splice_region
• Scores: Splicing: ADA: 0.1157
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.71

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-108598702-G-A is Pathogenic according to our data. Variant chrX-108598702-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1780G>A	p.Gly594Ser	missense_variant, splice_region_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.1780G>A	p.Gly594Ser	missense_variant, splice_region_variant	25/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.604G>A	p.Gly202Ser	missense_variant, splice_region_variant	9/20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.1780G>A	p.Gly594Ser	missense_variant, splice_region_variant	25/51	2		ENSP00000354505.2

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	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	.;D;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.0	D;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.042	D;D;.
Polyphen		0.56, 0.66	.;P;P
Vest4		0.71
MutPred		0.97		Gain of glycosylation at G594 (P = 0.0017);Gain of glycosylation at G594 (P = 0.0017);.;
MVP		0.99
MPC		0.30
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.28
SpliceAI score (max)		0.11		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: rs104886131; hg19: chrX-107841932;