chr9-134642252-CGCTGCT-C

Variant names:

• chr9-134642252-CGCTGCT-C
• rs773994971
• NM_000093.5:c.79_84delCTGCTG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP3

The NM_000093.5(COL5A1):​c.79_84delCTGCTG​(p.Leu27_Leu28del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,119,972 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: COL5A1 NM_000093.5 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 10 uncertain in NM_000093.5
• BP3: Nonframeshift variant in repetitive region in NM_000093.5

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000093.5. 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
	COL5A1	NM_000093.5	MANE Select	c.79_84delCTGCTG	p.Leu27_Leu28del	conservative_inframe_deletion	Exon 1 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.79_84delCTGCTG	p.Leu27_Leu28del	conservative_inframe_deletion	Exon 1 of 66	NP_001265003.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.79_84delCTGCTG	p.Leu27_Leu28del	conservative_inframe_deletion	Exon 1 of 66	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.79_84delCTGCTG	p.Leu27_Leu28del	conservative_inframe_deletion	Exon 1 of 66	ENSP00000360885.4
	COL5A1	ENST00000950240.1		c.79_84delCTGCTG	p.Leu27_Leu28del	conservative_inframe_deletion	Exon 1 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 43910 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000223 AC: 25 AN: 1119972 Hom.: 0 AF XY: 0.0000331 AC XY: 18 AN XY: 543114

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000437 AC: 1 AN: 22900

American (AMR) AF: 0.0000607 AC: 1 AN: 16462

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 23482

South Asian (SAS) AF: 0.000197 AC: 7 AN: 35476

European-Finnish (FIN) AF: 0.0000858 AC: 2 AN: 23320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3102

European-Non Finnish (NFE) AF: 0.0000128 AC: 12 AN: 934134

Other (OTH) AF: 0.0000455 AC: 2 AN: 43956

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome, classic type, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0

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;