rs786200923

Variant names:

• chr9-134835204-TGTGA-T
• rs786200923
• NM_000093.5:c.5370+3_5370+6delGAGT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The ENST00000371817.8(COL5A1):​c.5370+1_5370+4delGTGA variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002242973: RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 ENST00000371817.8 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.51
• Publications: 0 publications found

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

COL5A1 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arterial disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

LOC101448202 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.042414356 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002242973: RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.; SCV005983718: RNA studies demonstrated that this alteration results in abnormal splicing (Wenstrup RJ et al. Hum. Mol. Genet. 1996 Nov;5(11):1733-6).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-134835204-TGTGA-T is Pathogenic according to our data. Variant chr9-134835204-TGTGA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371817.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.5370+3_5370+6delGAGT		splice_region intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.5370+3_5370+6delGAGT		splice_region intron	N/A	NP_001265003.1	P20908-2
	LOC101448202	NR_103451.2		n.71-14999_71-14996delTCAC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.5370+1_5370+4delGTGA		splice_donor splice_region intron	N/A	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.5370+1_5370+4delGTGA		splice_donor splice_region intron	N/A	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.5361+1_5361+4delGTGA		splice_donor splice_region intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Ehlers-Danlos syndrome, classic type, 1 (2)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 0

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

Other links and lift over

dbSNP: rs786200923; hg19: chr9-137727050;