rs61735045

Variant names:

• chr9-134750808-G-A
• rs61735045
• NM_000093.5:c.1588G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-134750808-G-A
• chr9-134750808-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000093.5(COL5A1):​c.1588G>A​(p.Gly530Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,613,134 control chromosomes in the GnomAD database, including 1,546 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. G530G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (111 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1435 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: 7.24
• Publications: 30 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056170523).
• BP6: Variant 9-134750808-G-A is Benign according to our data. Variant chr9-134750808-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 38863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0317 (4824/152296) while in subpopulation NFE AF = 0.0477 (3242/68020). AF 95% confidence interval is 0.0463. There are 111 homozygotes in GnomAd4. There are 2243 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4824 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.1588G>A	p.Gly530Ser	missense	Exon 13 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.1588G>A	p.Gly530Ser	missense	Exon 13 of 66	NP_001265003.1	P20908-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.1588G>A	p.Gly530Ser	missense	Exon 13 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.1588G>A	p.Gly530Ser	missense	Exon 13 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.1579G>A	p.Gly527Ser	missense	Exon 13 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.0317 AC: 4827 AN: 152178 Hom.: 111 Cov.: 33

Gnomad AFR AF: 0.00770

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0313

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0476

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0347 AC: 8689 AN: 250360 AF XY: 0.0365

Gnomad AFR exome AF: 0.00744

Gnomad AMR exome AF: 0.0231

Gnomad ASJ exome AF: 0.0282

Gnomad EAS exome AF: 0.000762

Gnomad FIN exome AF: 0.0346

Gnomad NFE exome AF: 0.0469

Gnomad OTH exome AF: 0.0357

GnomAD4 exome AF: 0.0418 AC: 61014 AN: 1460838 Hom.: 1435 Cov.: 33 AF XY: 0.0419 AC XY: 30477 AN XY: 726732

African (AFR) AF: 0.00636 AC: 213 AN: 33480

American (AMR) AF: 0.0248 AC: 1107 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 765 AN: 26136

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39698

South Asian (SAS) AF: 0.0378 AC: 3262 AN: 86252

European-Finnish (FIN) AF: 0.0331 AC: 1741 AN: 52544

Middle Eastern (MID) AF: 0.0394 AC: 227 AN: 5768

European-Non Finnish (NFE) AF: 0.0461 AC: 51291 AN: 1111856

Other (OTH) AF: 0.0394 AC: 2381 AN: 60384

GnomAD4 genome AF: 0.0317 AC: 4824 AN: 152296 Hom.: 111 Cov.: 33 AF XY: 0.0301 AC XY: 2243 AN XY: 74464

African (AFR) AF: 0.00767 AC: 319 AN: 41576

American (AMR) AF: 0.0312 AC: 478 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5162

South Asian (SAS) AF: 0.0387 AC: 187 AN: 4830

European-Finnish (FIN) AF: 0.0325 AC: 345 AN: 10616

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0477 AC: 3242 AN: 68020

Other (OTH) AF: 0.0407 AC: 86 AN: 2112

Alfa AF: 0.0402 Hom.: 253

Bravo AF: 0.0301

TwinsUK AF: 0.0526 AC: 195

ALSPAC AF: 0.0444 AC: 171

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.0433 AC: 372

ExAC AF: 0.0353 AC: 4291

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0492

EpiControl AF: 0.0515

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	3	Ehlers-Danlos syndrome, classic type, 1 (3)
-	-	1	Connective tissue disorder (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type (2)
-	-	1	Ehlers-Danlos syndrome, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal (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
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Benign	0.094	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0056	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.88	L
PhyloP100		7.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.49
Sift	Benign	0.28	T
Sift4G	Benign	0.27	T
Polyphen		1.0	D
Vest4		0.23
MPC		1.5
ClinPred		0.031	T
GERP RS		4.5
Varity_R		0.10
gMVP		0.90
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs61735045; hg19: chr9-137642654; COSMIC: COSV65667766;