rs281874667

Positions:

• chrX-108591644-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_033380.3(COL4A5):​c.1423G>A​(p.Gly475Ser) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant X-108591644-G-A is Pathogenic according to our data. Variant chrX-108591644-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108591644-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.1423G>A	p.Gly475Ser	missense_variant, splice_region_variant	21/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1423G>A	p.Gly475Ser	missense_variant, splice_region_variant	21/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.247G>A	p.Gly83Ser	missense_variant, splice_region_variant	5/20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.1423G>A	p.Gly475Ser	missense_variant, splice_region_variant	21/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 475 of the COL4A5 protein (p.Gly475Ser). This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 20378821; Invitae). ClinVar contains an entry for this variant (Variation ID: 24409). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 is associated with inconclusive levels of altered splicing (PMID: 35005319). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

X-linked Alport syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Feb 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	34
DANN	Benign	0.97
DEOGEN2	Uncertain	0.73	.;D;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.7	D;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.86
MutPred		0.77		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);.;
MVP		1.0
MPC		0.30
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.95
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.80		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: rs281874667; hg19: chrX-107834874; COSMIC: COSV104653245;