rs104886372

Variant names:

• chrX-108624235-G-A
• rs104886372
• NM_033380.3:c.2918-1G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-108624235-G-A
• chrX-108624235-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_033380.3(COL4A5):​c.2918-1G>A variant causes a splice acceptor, intron 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: 24)
• Consequence: COL4A5 NM_033380.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.90
• Publications: 1 publications found

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]

COL4A5 Gene-Disease associations (from GenCC):

• Alport syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.019503547 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108624235-G-A is Pathogenic according to our data. Variant chrX-108624235-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 587182.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2918-1G>A		splice_acceptor_variant, intron_variant	Intron 33 of 52	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2918-1G>A		splice_acceptor_variant, intron_variant	Intron 33 of 52	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1742-1G>A		splice_acceptor_variant, intron_variant	Intron 17 of 19	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2918-1G>A		splice_acceptor_variant, intron_variant	Intron 33 of 50	2		ENSP00000354505.2
COL4A5	ENST00000505728.1	c.149-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 4	3		ENSP00000424137.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Alport syndrome Pathogenic:2

Mar 11, 2020

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous splice site variation in intron 33 of the COL4A5 gene was detected. The observed variant c.c.2918-1G>A has not been reported in the 1000 genomes and ExAC databases. It is reported in patient affected with Alport syndrome by Moriniere et al. 2014. The in silico prediction of the variant is damaging by MutationTaster2. In summary, the variant meets our criteria to be classified as pathogenic.

Dec 31, 2019

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A hemizygous 3' splice site variation in intron 33 of the COL4A5 gene that affects the invariant AG acceptor splice site of exon 34 was detected. The observed variant c.2918-1G>A (3' splice site) has previously been reported in patients affected with Alport syndrome (Moriniere et al 2014). The variant has not been reported in the 1000 Genomes and ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference base is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.0	.;.;.
MetaRNN	Benign	0.0	.;.;.
MutationAssessor	Benign	0.0	.;.;.
PhyloP100		8.9
PROVEAN	Benign	0.0	.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.
Sift4G	Pathogenic	0.0	.;.;.
Vest4		0.0
GERP RS		5.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 2
DS_AL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs104886372; hg19: chrX-107867465;