9-134642252-CGCTGCTGCT-CGCTGCTGCTGCTGCTGCT

Variant names:

• chr9-134642252-C-CGCTGCTGCT
• rs773994971
• NM_000093.5:c.76_84dupCTGCTGCTG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BS2

The NM_000093.5(COL5A1):​c.76_84dupCTGCTGCTG​(p.Leu26_Leu28dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000536 in 1,120,270 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000054 (0 hom.)
• Consequence: COL5A1 NM_000093.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.96
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 8 uncertain in NM_000093.5
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.76_84dupCTGCTGCTG	p.Leu26_Leu28dup	conservative_inframe_insertion	Exon 1 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.76_84dupCTGCTGCTG	p.Leu26_Leu28dup	conservative_inframe_insertion	Exon 1 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.76_84dupCTGCTGCTG	p.Leu26_Leu28dup	conservative_inframe_insertion	Exon 1 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.76_84dupCTGCTGCTG	p.Leu26_Leu28dup	conservative_inframe_insertion	Exon 1 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.76_84dupCTGCTGCTG	p.Leu26_Leu28dup	conservative_inframe_insertion	Exon 1 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000536 AC: 6 AN: 1120270 Hom.: 0 Cov.: 22 AF XY: 0.00000552 AC XY: 3 AN XY: 543276

African (AFR) AF: 0.00 AC: 0 AN: 22902

American (AMR) AF: 0.00 AC: 0 AN: 16478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17140

East Asian (EAS) AF: 0.0000426 AC: 1 AN: 23492

South Asian (SAS) AF: 0.00 AC: 0 AN: 35500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3106

European-Non Finnish (NFE) AF: 0.00000535 AC: 5 AN: 934364

Other (OTH) AF: 0.00 AC: 0 AN: 43966

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Dec 09, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In-frame insertion of 3 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -

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

Oct 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.76_84dup, results in the insertion of 3 amino acid(s) to the COL5A1 protein (p.Leu26_Leu28dup), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with COL5A1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=79/21	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs773994971; hg19: chr9-137534098;