chr9-134820151-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -4.64

Publications

18 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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL5A1	NM_000093.5 link	c.4482G>A	p.Pro1494Pro	synonymous_variant	Exon 58 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 link	c.4482G>A	p.Pro1494Pro	synonymous_variant	Exon 58 of 66		NP_001265003.1
COL5A1	XM_017014266.3 link	c.4482G>A	p.Pro1494Pro	synonymous_variant	Exon 58 of 65		XP_016869755.1
LOC101448202	NR_103451.2 link	n.129C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.4482G>A	p.Pro1494Pro	synonymous_variant	Exon 58 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4 link	c.4482G>A	p.Pro1494Pro	synonymous_variant	Exon 58 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes

AF:

0.0392

AC:

5969

AN:

152078

Hom.:

156

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0487

AC XY:

35381

AN XY:

727102

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

3747

7494

11242

14989

18736

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2170

4340

6510

8680

10850

<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:

0.0392

AC:

5967

AN:

152196

Hom.:

156

Cov.:

AF XY:

0.0391

AC XY:

2910

AN XY:

74402

show subpopulations

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:

AN:

5170

South Asian (SAS)

AF:

0.0180

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0753

AC:

798

AN:

10604

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0575

AC:

3906

AN:

67978

Other (OTH)

AF:

0.0365

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

295

590

885

1180

1475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0475

Hom.:

271

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Nov 12, 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.

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 20, 2015

Eurofins Ntd Llc (ga)

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 COL5A1 c.4482G>A (p.Pro1494Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools suggest on a creation of a new cryptic donor-accepter pair. ESE finder predicts that this variant may eliminate an SF2/ASF ESE site at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 5251/121210 control chromosomes (182 homozygotes) at a frequency of 0.0433215, which is approximately 34657 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. The variant has been cited in at least one publication and was described by the authors as a common polymorphism (Symoens_HM_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is 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

Sep 29, 2016

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 16, 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

-0.76

CADD

Benign

1.6

(source)

DANN

Benign

0.62

PhyloP100

-4.6

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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