9-134730403-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000093.5(COL5A1):c.1092C>T(p.Pro364Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 1,614,132 control chromosomes in the GnomAD database, including 2,976 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. P364P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.079 ( 1217 hom., cov: 34)

Exomes 𝑓: 0.023 ( 1759 hom. )

Consequence

COL5A1
NM_000093.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.31

Publications

9 publications found

Variant links:

COSMIC-nc: COSV65666942

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 9-134730403-C-T is Benign according to our data. Variant chr9-134730403-C-T is described in ClinVar as Benign. ClinVar VariationId is 136927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5 link	c.1092C>T	p.Pro364Pro	synonymous_variant	Exon 7 of 66	ENST00000371817.8	NP_000084.3	P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1	NM_001278074.1 link	c.1092C>T	p.Pro364Pro	synonymous_variant	Exon 7 of 66		NP_001265003.1	B2ZZ86Q59EE7
COL5A1	XM_017014266.3 link	c.1092C>T	p.Pro364Pro	synonymous_variant	Exon 7 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.1092C>T	p.Pro364Pro	synonymous_variant	Exon 7 of 66	1	NM_000093.5	ENSP00000360882.3		P20908-1
COL5A1	ENST00000371820.4 link	c.1092C>T	p.Pro364Pro	synonymous_variant	Exon 7 of 66	2		ENSP00000360885.4		P20908-2H7BY82

Frequencies

GnomAD3 genomes

AF:

0.0787

AC:

11974

AN:

152164

Hom.:

1207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.238

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0301

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00327

Gnomad SAS

AF:

0.120

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.0578

GnomAD2 exomes

AF:

0.0386

AC:

9704

AN:

251280

AF XY:

0.0380

show subpopulations

Gnomad AFR exome

AF:

0.241

Gnomad AMR exome

AF:

0.0176

Gnomad ASJ exome

AF:

0.00774

Gnomad EAS exome

AF:

0.00386

Gnomad FIN exome

AF:

0.0128

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.0240

GnomAD4 exome

AF:

0.0226

AC:

33033

AN:

1461850

Hom.:

1759

Cov.:

AF XY:

0.0241

AC XY:

17532

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.245

AC:

8205

AN:

33480

American (AMR)

AF:

0.0190

AC:

851

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00635

AC:

166

AN:

26136

East Asian (EAS)

AF:

0.00259

AC:

103

AN:

39700

South Asian (SAS)

AF:

0.108

AC:

9325

AN:

86256

European-Finnish (FIN)

AF:

0.0143

AC:

763

AN:

53378

Middle Eastern (MID)

AF:

0.0234

AC:

135

AN:

5768

European-Non Finnish (NFE)

AF:

0.0103

AC:

11506

AN:

1112012

Other (OTH)

AF:

0.0328

AC:

1979

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

2004

4008

6011

8015

10019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.0788

AC:

12005

AN:

152282

Hom.:

1217

Cov.:

AF XY:

0.0768

AC XY:

5720

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.238

AC:

9884

AN:

41518

American (AMR)

AF:

0.0300

AC:

460

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.00327

AC:

AN:

5192

South Asian (SAS)

AF:

0.120

AC:

580

AN:

4824

European-Finnish (FIN)

AF:

0.0105

AC:

112

AN:

10624

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0118

AC:

800

AN:

68024

Other (OTH)

AF:

0.0572

AC:

121

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

500

1000

1500

2000

2500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0464

Hom.:

321

Bravo

AF:

0.0859

Asia WGS

AF:

0.0700

AC:

243

AN:

3478

EpiCase

AF:

0.0107

EpiControl

AF:

0.0106

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

BA1 -

Nov 16, 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.1092C>T (p.Pro364Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 5362/121014 control chromosomes (451 homozygotes) at a frequency of 0.0443089, which is approximately 35447 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. 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

Feb 03, 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

Mar 02, 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.8

(source)

DANN

Benign

0.71

PhyloP100

-2.3

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over