9-134727349-C-T

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.738C>T(p.Thr246Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,612,790 control chromosomes in the GnomAD database, including 154,153 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. T246T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.36 ( 11704 hom., cov: 32)

Exomes 𝑓: 0.44 ( 142449 hom. )

Consequence

COL5A1
NM_000093.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -6.56

Publications

24 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:

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=-0.84).

BP6

Variant 9-134727349-C-T is Benign according to our data. Variant chr9-134727349-C-T is described in ClinVar as Benign. ClinVar VariationId is 136922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL5A1	NM_000093.5 link	c.738C>T	p.Thr246Thr	synonymous_variant	Exon 5 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 link	c.738C>T	p.Thr246Thr	synonymous_variant	Exon 5 of 66		NP_001265003.1
COL5A1	XM_017014266.3 link	c.738C>T	p.Thr246Thr	synonymous_variant	Exon 5 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 link	c.738C>T	p.Thr246Thr	synonymous_variant	Exon 5 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4 link	c.738C>T	p.Thr246Thr	synonymous_variant	Exon 5 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes

AF:

0.357

AC:

54224

AN:

151840

Hom.:

11694

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.336

Gnomad AMR

AF:

0.505

Gnomad ASJ

AF:

0.618

Gnomad EAS

AF:

0.405

Gnomad SAS

AF:

0.433

Gnomad FIN

AF:

0.466

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.417

GnomAD2 exomes

AF:

0.446

AC:

112095

AN:

251418

AF XY:

0.447

show subpopulations

Gnomad AFR exome

AF:

0.0903

Gnomad AMR exome

AF:

0.601

Gnomad ASJ exome

AF:

0.619

Gnomad EAS exome

AF:

0.394

Gnomad FIN exome

AF:

0.470

Gnomad NFE exome

AF:

0.441

Gnomad OTH exome

AF:

0.466

GnomAD4 exome

AF:

0.436

AC:

637131

AN:

1460832

Hom.:

142449

Cov.:

AF XY:

0.437

AC XY:

317516

AN XY:

726750

show subpopulations

African (AFR)

AF:

0.0859

AC:

2875

AN:

33478

American (AMR)

AF:

0.590

AC:

26404

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.620

AC:

16212

AN:

26134

East Asian (EAS)

AF:

0.393

AC:

15616

AN:

39690

South Asian (SAS)

AF:

0.432

AC:

37274

AN:

86236

European-Finnish (FIN)

AF:

0.470

AC:

25082

AN:

53402

Middle Eastern (MID)

AF:

0.471

AC:

2717

AN:

5768

European-Non Finnish (NFE)

AF:

0.436

AC:

484745

AN:

1111044

Other (OTH)

AF:

0.434

AC:

26206

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

19002

38005

57007

76010

95012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14686

29372

44058

58744

73430

<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:

0.357

AC:

54239

AN:

151958

Hom.:

11704

Cov.:

AF XY:

0.364

AC XY:

26998

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.102

AC:

4250

AN:

41472

American (AMR)

AF:

0.506

AC:

7727

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.618

AC:

2142

AN:

3468

East Asian (EAS)

AF:

0.406

AC:

2092

AN:

5158

South Asian (SAS)

AF:

0.433

AC:

2086

AN:

4816

European-Finnish (FIN)

AF:

0.466

AC:

4912

AN:

10542

Middle Eastern (MID)

AF:

0.425

AC:

125

AN:

294

European-Non Finnish (NFE)

AF:

0.437

AC:

29713

AN:

67918

Other (OTH)

AF:

0.420

AC:

886

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1588

3176

4764

6352

7940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

518

1036

1554

2072

2590

<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:

0.412

Hom.:

31372

Bravo

AF:

0.351

Asia WGS

AF:

0.446

AC:

1546

AN:

3478

EpiCase

AF:

0.445

EpiControl

AF:

0.446

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Nov 13, 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

- -

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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.738C>T (p.Thr246Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. The variant is not found within a known functional domain and one in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not significantly affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 52060/121340 control chromosomes (12029 homozygotes) at a frequency of 0.4290424, which is approximately 343234 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. Several publications have cited the variant as a common polymorphism (Symoens_HM_2012; Takahara_AJHG_2002). 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

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

Dec 29, 2014

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

-0.84

CADD

Benign

0.0040

(source)

DANN

Benign

0.39

PhyloP100

-6.6

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