9-134641909-TGGAGGAGGA-TGGAGGAGGAGGA

Variant names:

• chr9-134641909-T-TGGA
• rs886063671
• NM_000093.5:c.-261_-259dupAGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000093.5(COL5A1):​c.-261_-259dupAGG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000046 in 369,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: COL5A1 NM_000093.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0930
• 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: Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• 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 -4 ACMG points.

• BS2: High AC in GnomAd4 at 8 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.-261_-259dupAGG		5_prime_UTR	Exon 1 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.-261_-259dupAGG		5_prime_UTR	Exon 1 of 66	NP_001265003.1	P20908-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.-261_-259dupAGG		5_prime_UTR	Exon 1 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.-261_-259dupAGG		5_prime_UTR	Exon 1 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.-279_-278insGGA		upstream_gene	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.0000534 AC: 8 AN: 149842 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000986

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000404

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 9 AN: 219774 Hom.: 0 Cov.: 0 AF XY: 0.0000446 AC XY: 5 AN XY: 112022

African (AFR) AF: 0.00 AC: 0 AN: 6222

American (AMR) AF: 0.00 AC: 0 AN: 6518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8052

East Asian (EAS) AF: 0.00 AC: 0 AN: 20624

South Asian (SAS) AF: 0.00 AC: 0 AN: 2730

European-Finnish (FIN) AF: 0.0000525 AC: 1 AN: 19056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1164

European-Non Finnish (NFE) AF: 0.0000568 AC: 8 AN: 140934

Other (OTH) AF: 0.00 AC: 0 AN: 14474

GnomAD4 genome AF: 0.0000534 AC: 8 AN: 149842 Hom.: 0 Cov.: 34 AF XY: 0.0000821 AC XY: 6 AN XY: 73102

African (AFR) AF: 0.0000986 AC: 4 AN: 40586

American (AMR) AF: 0.00 AC: 0 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000404 AC: 2 AN: 4952

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67340

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome type 7A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.093
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs886063671; hg19: chr9-137533755;