9-134820151-G-C

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>C(p.Pro1494Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,613,406 control chromosomes in the GnomAD database, including 109,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1494P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.39 ( 12196 hom., cov: 33)

Exomes 𝑓: 0.36 ( 97508 hom. )

Consequence

COL5A1
NM_000093.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

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=-0.78).

BP6

Variant 9-134820151-G-C is Benign according to our data. Variant chr9-134820151-G-C is described in ClinVar as Benign. ClinVar VariationId is 136900.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 (AFR) allele frequency at 95% confidence interval = 0.489 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL5A1	NM_000093.5	MANE Select	c.4482G>C	p.Pro1494Pro	synonymous	Exon 58 of 66	NP_000084.3
COL5A1	NM_001278074.1		c.4482G>C	p.Pro1494Pro	synonymous	Exon 58 of 66	NP_001265003.1
LOC101448202	NR_103451.2		n.129C>G		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.4482G>C	p.Pro1494Pro	synonymous	Exon 58 of 66	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.4482G>C	p.Pro1494Pro	synonymous	Exon 58 of 66	ENSP00000360885.4

Frequencies

GnomAD3 genomes

AF:

0.394

AC:

59875

AN:

152034

Hom.:

12172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.495

Gnomad AMI

AF:

0.351

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.342

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.368

Gnomad FIN

AF:

0.341

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.365

Gnomad OTH

AF:

0.381

GnomAD2 exomes

AF:

0.369

AC:

92653

AN:

251342

AF XY:

0.368

show subpopulations

Gnomad AFR exome

AF:

0.504

Gnomad AMR exome

AF:

0.314

Gnomad ASJ exome

AF:

0.344

Gnomad EAS exome

AF:

0.385

Gnomad FIN exome

AF:

0.346

Gnomad NFE exome

AF:

0.366

Gnomad OTH exome

AF:

0.357

GnomAD4 exome

AF:

0.363

AC:

530889

AN:

1461254

Hom.:

97508

Cov.:

AF XY:

0.364

AC XY:

264673

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.505

AC:

16890

AN:

33470

American (AMR)

AF:

0.313

AC:

14010

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

9014

AN:

26132

East Asian (EAS)

AF:

0.376

AC:

14938

AN:

39686

South Asian (SAS)

AF:

0.380

AC:

32819

AN:

86254

European-Finnish (FIN)

AF:

0.350

AC:

18657

AN:

53246

Middle Eastern (MID)

AF:

0.422

AC:

2435

AN:

5764

European-Non Finnish (NFE)

AF:

0.360

AC:

399990

AN:

1111604

Other (OTH)

AF:

0.367

AC:

22136

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

19419

38838

58258

77677

97096

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12686

25372

38058

50744

63430

<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:

0.394

AC:

59941

AN:

152152

Hom.:

12196

Cov.:

AF XY:

0.387

AC XY:

28790

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.495

AC:

20557

AN:

41524

American (AMR)

AF:

0.316

AC:

4826

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.342

AC:

1187

AN:

3472

East Asian (EAS)

AF:

0.379

AC:

1955

AN:

5164

South Asian (SAS)

AF:

0.367

AC:

1771

AN:

4828

European-Finnish (FIN)

AF:

0.341

AC:

3618

AN:

10606

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.365

AC:

24797

AN:

67968

Other (OTH)

AF:

0.384

AC:

810

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1894

3788

5681

7575

9469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

572

1144

1716

2288

2860

<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:

0.0297

Hom.:

271

EpiCase

AF:

0.358

EpiControl

AF:

0.356

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

Nov 02, 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.

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>C (p.Pro1494Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may eliminate an SC35 ESE site. However, these predictions have yet to be confirmed by functional studies. The variant lies within the collagen triple helix repeat domain of the protein (InterPro). This variant was found in 45450/121210 control chromosomes (8705 homozygotes) at a frequency of 0.3749691, which is approximately 299975 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant has been cited in at least one publication and was described by the authors as a common polymorphism (Symoens_HM_2012). Taken together, this variant is classified as benign.

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Ehlers-Danlos syndrome, classic type, 1

Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Fibromuscular dysplasia, multifocal

Benign:1

Jul 30, 2021

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 23, 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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.048

(source)

DANN

Benign

0.55

PhyloP100

-4.6

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over