rs104886300

Positions:

• chrX-108694921-G-A
• chrX-108694921-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_033380.3(COL4A5):​c.4821G>A​(p.Met1607Ile) 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 16 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-108694921-G-A is Pathogenic according to our data. Variant chrX-108694921-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 24773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108694921-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.4821G>A	p.Met1607Ile	missense_variant, splice_region_variant	51/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.4821G>A	p.Met1607Ile	missense_variant, splice_region_variant	51/53	1	NM_033380.3	ENSP00000331902

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 08, 2022	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1601 of the COL4A5 protein (p.Met1601Ile). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 8510391, 10094548, 20378821). ClinVar contains an entry for this variant (Variation ID: 24773). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 49 and introduces a premature termination codon (PMID: 10094548). The resulting mRNA is expected to undergo nonsense-mediated decay. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.90
MutPred		0.74		.;Loss of catalytic residue at M1600 (P = 0.0433);.;
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.71		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104886300; hg19: chrX-107938151;