rs1060502250

chr9-134834972-TCTC-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM4_Supporting PP3 PP5_Moderate

The NM_000093.5(COL5A1):c.5141_5143del(p.Ser1714del) variant causes a inframe deletion, splice region change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L1713L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 NM_000093.5 inframe_deletion, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.85

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]

LOC101448202 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000093.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-134834972-TCTC-T is Pathogenic according to our data. Variant chr9-134834972-TCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 409098.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.5141_5143del	p.Ser1714del	inframe_deletion, splice_region_variant	65/66	ENST00000371817.8
LOC101448202	NR_103451.2	n.71-14766_71-14764del		intron_variant, non_coding_transcript_variant
COL5A1	NM_001278074.1	c.5141_5143del	p.Ser1714del	inframe_deletion, splice_region_variant	65/66
COL5A1	XM_017014266.3			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.5141_5143del	p.Ser1714del	inframe_deletion, splice_region_variant	65/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.5141_5143del	p.Ser1714del	inframe_deletion, splice_region_variant	65/66	2		A2

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 07, 2016

Family studies have indicated that this variant was not present in the parents of an individual with classical Ehlers-Danlos syndrome, which suggests that it was de novo in that affected individual (Invitae). In summary, this variant is a novel in-frame deletion with uncertain impact on protein function. Because it has been observed as arising de novo in an affected individual, it has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL5A1-related disease. This sequence change deletes 3 nucleotides from exon 65 of the COL5A1 mRNA (c.5141_5143delCCT). This leads to the deletion of 1 amino acid residue in the COL5A1 protein (p.Ser1714del) but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060502250; hg19: chr9-137726818;