9-134642252-CGCT-C

Variant names:

• chr9-134642252-CGCT-C
• rs773994971
• NM_000093.5:c.82_84delCTG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP3 BP6

The NM_000093.5(COL5A1):​c.82_84delCTG​(p.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 0.00323 in 1,249,090 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L28L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (0 hom.)
• Consequence: COL5A1 NM_000093.5 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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 0 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, 9 uncertain in NM_000093.5
• BP3: Nonframeshift variant in repetitive region in NM_000093.5
• BP6: Variant 9-134642252-CGCT-C is Benign according to our data. Variant chr9-134642252-CGCT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 570337.

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.82_84delCTG	p.Leu28del	conservative_inframe_deletion	Exon 1 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.82_84delCTG	p.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.82_84delCTG	p.Leu28del	conservative_inframe_deletion	Exon 1 of 66	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.82_84delCTG	p.Leu28del	conservative_inframe_deletion	Exon 1 of 66	ENSP00000360885.4
	COL5A1	ENST00000950240.1		c.82_84delCTG	p.Leu28del	conservative_inframe_deletion	Exon 1 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.0000467 AC: 7 AN: 149912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000204

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000594

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.0102 AC: 450 AN: 43910 AF XY: 0.00967

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.00999

Gnomad ASJ exome AF: 0.00869

Gnomad EAS exome AF: 0.00971

Gnomad FIN exome AF: 0.0115

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00366 AC: 4023 AN: 1099178 Hom.: 0 AF XY: 0.00397 AC XY: 2114 AN XY: 532712

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

African (AFR) AF: 0.00276 AC: 62 AN: 22476

American (AMR) AF: 0.00550 AC: 89 AN: 16180

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 90 AN: 16784

East Asian (EAS) AF: 0.00228 AC: 52 AN: 22854

South Asian (SAS) AF: 0.00810 AC: 282 AN: 34820

European-Finnish (FIN) AF: 0.00326 AC: 74 AN: 22690

Middle Eastern (MID) AF: 0.00360 AC: 11 AN: 3052

European-Non Finnish (NFE) AF: 0.00350 AC: 3208 AN: 917300

Other (OTH) AF: 0.00360 AC: 155 AN: 43022

⚠️ 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 AF: 0.0000467 AC: 7 AN: 149912 Hom.: 0 Cov.: 32 AF XY: 0.0000684 AC XY: 5 AN XY: 73116

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

African (AFR) AF: 0.00 AC: 0 AN: 41114

American (AMR) AF: 0.00 AC: 0 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000204 AC: 2 AN: 9800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000594 AC: 4 AN: 67306

Other (OTH) AF: 0.000486 AC: 1 AN: 2056

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs773994971; hg19: chr9-137534098;