rs104886434

Variant names:

• chrX-108575973-G-A
• rs104886434
• NM_033380.3:c.609+1G>A

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.609+1G>A variant causes a splice donor, 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: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: COL4A5 NM_033380.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.92
• 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 0.012411348 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.1, offset of -8, new splice context is: cagGTttga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108575973-G-A is Pathogenic according to our data. Variant chrX-108575973-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1804103.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.609+1G>A		splice_donor intron	N/A	NP_203699.1
	COL4A5	NM_000495.5		c.609+1G>A		splice_donor intron	N/A	NP_000486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.609+1G>A		splice_donor intron	N/A	ENSP00000331902.7
	COL4A5	ENST00000361603.7	TSL:2	c.609+1G>A		splice_donor intron	N/A	ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1043933 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 317637

African (AFR) AF: 0.00 AC: 0 AN: 25415

American (AMR) AF: 0.00 AC: 0 AN: 34758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18942

East Asian (EAS) AF: 0.00 AC: 0 AN: 29592

South Asian (SAS) AF: 0.00 AC: 0 AN: 51593

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4007

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 795458

Other (OTH) AF: 0.00 AC: 0 AN: 44172

GnomAD4 genome Cov.: 22

Alfa AF: 0.000871 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	X-linked Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.9
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	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -1

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

Other links and lift over

dbSNP: rs104886434; hg19: chrX-107819203;