rs104886305

Positions:

• chrX-108695439-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_033380.3(COL4A5):​c.4994G>A​(p.Ser1665Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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, single submitter P:1
• Conservation: PhyloP100: 5.56

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 10 ACMG points.

• PM1: In a disulfide_bond Or C-1586 with C-1678 (size 95) in uniprot entity CO4A5_HUMAN there are 16 pathogenic changes around while only 5 benign (76%) 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-108695439-G-A is Pathogenic according to our data. Variant chrX-108695439-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1443814.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108695439-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.4994G>A	p.Ser1665Asn	missense_variant, splice_region_variant	52/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.4994G>A	p.Ser1665Asn	missense_variant, splice_region_variant	52/53	1	NM_033380.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 10, 2021

For these reasons, this variant has been classified as Pathogenic. 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 50 and introduces a new termination codon (PMID: 8940267). However the mRNA is not expected to undergo nonsense-mediated decay. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 24782). This variant is also known as 5178G>A. This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 8940267, 22921432; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 1659 of the COL4A5 protein (p.Ser1659Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.65	T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.81	N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.95	.;P
Vest4		0.21
MutPred		0.42		.;Gain of catalytic residue at S1659 (P = 0.0431);
MVP		0.85
MPC		0.90
ClinPred		0.90	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		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: rs104886305; hg19: chrX-107938669;