rs2228559

Variant names:

• chr9-134822102-C-T
• rs2228559
• NM_000093.5:c.4560C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000093.5(COL5A1):​c.4560C>T​(p.Ile1520Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,196 control chromosomes in the GnomAD database, including 793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (118 hom., cov: 33)
  • Exomes 𝑓: 0.028 (675 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.368
• Publications: 3 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

LOC101448202 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 9-134822102-C-T is Benign according to our data. Variant chr9-134822102-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.368 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0619 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.4560C>T	p.Ile1520Ile	synonymous	Exon 59 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.4560C>T	p.Ile1520Ile	synonymous	Exon 59 of 66	NP_001265003.1	P20908-2
	LOC101448202	NR_103451.2		n.71-1893G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.4560C>T	p.Ile1520Ile	synonymous	Exon 59 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.4560C>T	p.Ile1520Ile	synonymous	Exon 59 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.4551C>T	p.Ile1517Ile	synonymous	Exon 59 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5305 AN: 152166 Hom.: 116 Cov.: 33

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0364

GnomAD2 exomes AF: 0.0256 AC: 6429 AN: 251446 AF XY: 0.0250

Gnomad AFR exome AF: 0.0654

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0503

Gnomad EAS exome AF: 0.00103

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.0287

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0278 AC: 40627 AN: 1460912 Hom.: 675 Cov.: 32 AF XY: 0.0275 AC XY: 19976 AN XY: 726792

African (AFR) AF: 0.0665 AC: 2226 AN: 33450

American (AMR) AF: 0.0127 AC: 566 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 1341 AN: 26122

East Asian (EAS) AF: 0.000781 AC: 31 AN: 39698

South Asian (SAS) AF: 0.0166 AC: 1435 AN: 86234

European-Finnish (FIN) AF: 0.0216 AC: 1154 AN: 53378

Middle Eastern (MID) AF: 0.0398 AC: 228 AN: 5730

European-Non Finnish (NFE) AF: 0.0286 AC: 31832 AN: 1111228

Other (OTH) AF: 0.0301 AC: 1814 AN: 60356

GnomAD4 genome AF: 0.0349 AC: 5311 AN: 152284 Hom.: 118 Cov.: 33 AF XY: 0.0327 AC XY: 2436 AN XY: 74464

African (AFR) AF: 0.0639 AC: 2657 AN: 41556

American (AMR) AF: 0.0167 AC: 255 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 184 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5172

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4826

European-Finnish (FIN) AF: 0.0205 AC: 218 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0271 AC: 1843 AN: 68024

Other (OTH) AF: 0.0360 AC: 76 AN: 2112

Alfa AF: 0.0309 Hom.: 47

Bravo AF: 0.0354

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.0218

EpiControl AF: 0.0248

ClinVar

ClinVar submissions

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, 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	-0.33
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		0.37
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: rs2228559; hg19: chr9-137713948;