rs2228559

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.368

Publications

3 publications found

Variant links:

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

COL5A1 links:

LOC101448202 (HGNC:):

LOC101448202 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL5A1	NM_000093.5 link	c.4560C>T	p.Ile1520Ile	synonymous_variant	Exon 59 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 link	c.4560C>T	p.Ile1520Ile	synonymous_variant	Exon 59 of 66		NP_001265003.1
COL5A1	XM_017014266.3 link	c.4560C>T	p.Ile1520Ile	synonymous_variant	Exon 59 of 65		XP_016869755.1
LOC101448202	NR_103451.2 link	n.71-1893G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.4560C>T	p.Ile1520Ile	synonymous_variant	Exon 59 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4 link	c.4560C>T	p.Ile1520Ile	synonymous_variant	Exon 59 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes

AF:

0.0349

AC:

5305

AN:

152166

Hom.:

116

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0275

AC XY:

19976

AN XY:

726792

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

1953

3905

5858

7810

9763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1272

2544

3816

5088

6360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0349

AC:

5311

AN:

152284

Hom.:

118

Cov.:

AF XY:

0.0327

AC XY:

2436

AN XY:

74464

show subpopulations

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:

AN:

5172

South Asian (SAS)

AF:

0.0122

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0205

AC:

218

AN:

10612

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0271

AC:

1843

AN:

68024

Other (OTH)

AF:

0.0360

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

283

566

849

1132

1415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0309

Hom.:

Bravo

AF:

0.0354

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0218

EpiControl

AF:

0.0248

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 29, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Mar 15, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.4560C>T (p.Ile1520=) in COL5A1 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect the normal splicing pattern, however no functional studies supporting these predictions were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.02718 (3299 /121364 chrs tested), including numerous homozygous occurrences. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.000031). The variant of interest has been cited as Benign by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign.

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Ehlers-Danlos syndrome, classic type, 1

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 15, 2022

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Fibromuscular dysplasia, multifocal

Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jan 30, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Ehlers-Danlos syndrome type 7A

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ehlers-Danlos syndrome

Benign:1

Jul 07, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over