rs1554726245

Variant names:

• chr9-134834981-TGGACGCCGA-T
• rs1554726245
• NM_000093.5:c.5150_5158delACGCCGAGG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM4 PP3 PP5_Moderate

The NM_000093.5(COL5A1):​c.5150_5158delACGCCGAGG​(p.Asp1717_Glu1719del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. D1717D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 NM_000093.5 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.78
• 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: ClinGen, Orphanet, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000093.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-134834981-TGGACGCCGA-T is Pathogenic according to our data. Variant chr9-134834981-TGGACGCCGA-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 523326.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.5150_5158delACGCCGAGG	p.Asp1717_Glu1719del	disruptive_inframe_deletion	Exon 65 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.5150_5158delACGCCGAGG	p.Asp1717_Glu1719del	disruptive_inframe_deletion	Exon 65 of 66		NP_001265003.1
LOC101448202	NR_103451.2	n.71-14781_71-14773delTCGGCGTCC		intron_variant	Intron 1 of 1
COL5A1	XM_017014266.3	c.*2229_*2237delGGACGCCGA		downstream_gene_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.5150_5158delACGCCGAGG	p.Asp1717_Glu1719del	disruptive_inframe_deletion	Exon 65 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.5150_5158delACGCCGAGG	p.Asp1717_Glu1719del	disruptive_inframe_deletion	Exon 65 of 66	2		ENSP00000360885.4

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

Atrophic scars;C0241074:Hyperextensible skin;C1844820:Joint hypermobility;C1851828:Cigarette-paper scars;C4025260:Large joint dislocations Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.8

Splicing

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

Other links and lift over

dbSNP: rs1554726245; hg19: chr9-137726827;