rs116715381

Variant names:

• chr9-134701252-C-T
• rs116715381
• NM_000093.5:c.573C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000093.5(COL5A1):​c.573C>T​(p.Leu191Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,952 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.35
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 9-134701252-C-T is Benign according to our data. Variant chr9-134701252-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00297 (452/152274) while in subpopulation AFR AF = 0.007 (291/41566). AF 95% confidence interval is 0.00634. There are 1 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 452 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.573C>T	p.Leu191Leu	synonymous	Exon 4 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.573C>T	p.Leu191Leu	synonymous	Exon 4 of 66	NP_001265003.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.573C>T	p.Leu191Leu	synonymous	Exon 4 of 66	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.573C>T	p.Leu191Leu	synonymous	Exon 4 of 66	ENSP00000360885.4
	COL5A1	ENST00000950240.1		c.573C>T	p.Leu191Leu	synonymous	Exon 4 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 451 AN: 152156 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00290

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00191 AC: 479 AN: 250298 AF XY: 0.00162

Gnomad AFR exome AF: 0.00842

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00269

Gnomad EAS exome AF: 0.00435

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00111 AC: 1627 AN: 1461678 Hom.: 3 Cov.: 33 AF XY: 0.00107 AC XY: 775 AN XY: 727118

African (AFR) AF: 0.00806 AC: 270 AN: 33480

American (AMR) AF: 0.00255 AC: 114 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26130

East Asian (EAS) AF: 0.00363 AC: 144 AN: 39698

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86248

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53280

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.000740 AC: 823 AN: 1111972

Other (OTH) AF: 0.00235 AC: 142 AN: 60392

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152274 Hom.: 1 Cov.: 33 AF XY: 0.00291 AC XY: 217 AN XY: 74444

African (AFR) AF: 0.00700 AC: 291 AN: 41566

American (AMR) AF: 0.00451 AC: 69 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3466

East Asian (EAS) AF: 0.00291 AC: 15 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68030

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00195 Hom.: 1

Bravo AF: 0.00368

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00142

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Ehlers-Danlos syndrome, classic type (2)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.18
DANN	Benign	0.78
PhyloP100		-2.4
Mutation Taster		=100/0	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: rs116715381; hg19: chr9-137593098;