rs2228560

Variant names:

• chr9-134820151-G-A
• rs2228560
• NM_000093.5:c.4482G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-134820151-G-A
• chr9-134820151-G-C
• chr9-134820151-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000093.5(COL5A1):​c.4482G>A​(p.Pro1494Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,613,790 control chromosomes in the GnomAD database, including 2,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1494P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.039 (156 hom., cov: 33)
  • Exomes 𝑓: 0.049 (1960 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -4.64
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 9-134820151-G-A is Benign according to our data. Variant chr9-134820151-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.056 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.4482G>A	p.Pro1494Pro	synonymous	Exon 58 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.4482G>A	p.Pro1494Pro	synonymous	Exon 58 of 66	NP_001265003.1	P20908-2
	LOC101448202	NR_103451.2		n.129C>T		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.4482G>A	p.Pro1494Pro	synonymous	Exon 58 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.4482G>A	p.Pro1494Pro	synonymous	Exon 58 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.4473G>A	p.Pro1491Pro	synonymous	Exon 58 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.0392 AC: 5969 AN: 152078 Hom.: 156 Cov.: 33

Gnomad AFR AF: 0.00925

Gnomad AMI AF: 0.0386

Gnomad AMR AF: 0.0320

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0753

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0575

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0418 AC: 10509 AN: 251342 AF XY: 0.0421

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0438

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0742

Gnomad NFE exome AF: 0.0591

Gnomad OTH exome AF: 0.0478

GnomAD4 exome AF: 0.0493 AC: 72083 AN: 1461594 Hom.: 1960 Cov.: 47 AF XY: 0.0487 AC XY: 35381 AN XY: 727102

African (AFR) AF: 0.00750 AC: 251 AN: 33478

American (AMR) AF: 0.0223 AC: 996 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0440 AC: 1149 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39696

South Asian (SAS) AF: 0.0193 AC: 1669 AN: 86256

European-Finnish (FIN) AF: 0.0737 AC: 3926 AN: 53246

Middle Eastern (MID) AF: 0.0326 AC: 188 AN: 5768

European-Non Finnish (NFE) AF: 0.0550 AC: 61131 AN: 1111908

Other (OTH) AF: 0.0457 AC: 2759 AN: 60388

GnomAD4 genome AF: 0.0392 AC: 5967 AN: 152196 Hom.: 156 Cov.: 33 AF XY: 0.0391 AC XY: 2910 AN XY: 74402

African (AFR) AF: 0.00922 AC: 383 AN: 41538

American (AMR) AF: 0.0320 AC: 489 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 176 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5170

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4828

European-Finnish (FIN) AF: 0.0753 AC: 798 AN: 10604

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0575 AC: 3906 AN: 67978

Other (OTH) AF: 0.0365 AC: 77 AN: 2112

Alfa AF: 0.0475 Hom.: 271

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.76
CADD	Benign	1.6
DANN	Benign	0.62
PhyloP100		-4.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2228560; hg19: chr9-137711997; COSMIC: COSV65665652; COSMIC: COSV65665652;