rs12685946

Variant names:

• chr9-134750632-A-G
• rs12685946
• NM_000093.5:c.1569+16A>G

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.1569+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,612,112 control chromosomes in the GnomAD database, including 49,976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7388 hom., cov: 32)
  • Exomes 𝑓: 0.23 (42588 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.73
• Publications: 8 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=-0.94).
• BP6: Variant 9-134750632-A-G is Benign according to our data. Variant chr9-134750632-A-G is described in ClinVar as Benign. ClinVar VariationId is 136862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

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.1569+16A>G		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.1569+16A>G		intron	N/A	NP_001265003.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.1569+16A>G		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.1569+16A>G		intron	N/A	ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44030 AN: 151898 Hom.: 7381 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.243

GnomAD2 exomes AF: 0.228 AC: 57228 AN: 250686 AF XY: 0.223

Gnomad AFR exome AF: 0.480

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.346

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.229

Gnomad OTH exome AF: 0.204

GnomAD4 exome AF: 0.235 AC: 342867 AN: 1460096 Hom.: 42588 Cov.: 33 AF XY: 0.232 AC XY: 168366 AN XY: 726440

African (AFR) AF: 0.482 AC: 16137 AN: 33464

American (AMR) AF: 0.133 AC: 5955 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3647 AN: 26134

East Asian (EAS) AF: 0.325 AC: 12919 AN: 39696

South Asian (SAS) AF: 0.173 AC: 14904 AN: 86244

European-Finnish (FIN) AF: 0.231 AC: 12151 AN: 52518

Middle Eastern (MID) AF: 0.213 AC: 1226 AN: 5768

European-Non Finnish (NFE) AF: 0.236 AC: 261741 AN: 1111208

Other (OTH) AF: 0.235 AC: 14187 AN: 60346

GnomAD4 genome AF: 0.290 AC: 44064 AN: 152016 Hom.: 7388 Cov.: 32 AF XY: 0.285 AC XY: 21218 AN XY: 74330

African (AFR) AF: 0.468 AC: 19379 AN: 41436

American (AMR) AF: 0.181 AC: 2761 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3470

East Asian (EAS) AF: 0.330 AC: 1689 AN: 5124

South Asian (SAS) AF: 0.157 AC: 757 AN: 4828

European-Finnish (FIN) AF: 0.232 AC: 2453 AN: 10596

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.230 AC: 15612 AN: 67956

Other (OTH) AF: 0.240 AC: 508 AN: 2114

Alfa AF: 0.240 Hom.: 916

Bravo AF: 0.298

Asia WGS AF: 0.216 AC: 752 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	1	Fibromuscular dysplasia, multifocal (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0020
DANN	Benign	0.19
PhyloP100		-2.7
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: rs12685946; hg19: chr9-137642478; COSMIC: COSV65671897;