rs12005720

Variant names:

• chr9-134786174-T-C
• rs12005720
• NM_000093.5:c.2646+126T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.2646+126T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 927,386 control chromosomes in the GnomAD database, including 7,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1753 hom., cov: 32)
  • Exomes 𝑓: 0.12 (5989 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.49
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 9-134786174-T-C is Benign according to our data. Variant chr9-134786174-T-C is described in ClinVar as Benign. ClinVar VariationId is 1257326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.2646+126T>C		intron_variant	Intron 31 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2646+126T>C		intron_variant	Intron 31 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.2646+126T>C		intron_variant	Intron 31 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2646+126T>C		intron_variant	Intron 31 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.2646+126T>C		intron_variant	Intron 31 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21936 AN: 151868 Hom.: 1750 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0868

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.0728

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.147

GnomAD4 exome AF: 0.118 AC: 91139 AN: 775400 Hom.: 5989 AF XY: 0.116 AC XY: 46843 AN XY: 403004

African (AFR) AF: 0.207 AC: 3999 AN: 19330

American (AMR) AF: 0.0788 AC: 2587 AN: 32826

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 2532 AN: 20770

East Asian (EAS) AF: 0.139 AC: 4420 AN: 31858

South Asian (SAS) AF: 0.0789 AC: 5066 AN: 64192

European-Finnish (FIN) AF: 0.157 AC: 7381 AN: 46924

Middle Eastern (MID) AF: 0.105 AC: 446 AN: 4238

European-Non Finnish (NFE) AF: 0.116 AC: 60041 AN: 518250

Other (OTH) AF: 0.126 AC: 4667 AN: 37012

GnomAD4 genome AF: 0.144 AC: 21962 AN: 151986 Hom.: 1753 Cov.: 32 AF XY: 0.142 AC XY: 10545 AN XY: 74300

African (AFR) AF: 0.202 AC: 8383 AN: 41458

American (AMR) AF: 0.0868 AC: 1325 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 442 AN: 3464

East Asian (EAS) AF: 0.156 AC: 807 AN: 5172

South Asian (SAS) AF: 0.0722 AC: 347 AN: 4806

European-Finnish (FIN) AF: 0.158 AC: 1675 AN: 10578

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8636 AN: 67930

Other (OTH) AF: 0.146 AC: 307 AN: 2108

Alfa AF: 0.128 Hom.: 609

Bravo AF: 0.142

Asia WGS AF: 0.134 AC: 466 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.47
DANN	Benign	0.19
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs12005720; hg19: chr9-137678020; COSMIC: COSV65667109;