rs1800255

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000090.4(COL3A1):c.2092G>A(p.Ala698Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,598,508 control chromosomes in the GnomAD database, including 49,266 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A698S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.22 ( 3858 hom., cov: 32)

Exomes 𝑓: 0.25 ( 45408 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: 0.112

Publications

101 publications found

Variant links:

Genes affected

COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

COL3A1 Gene-Disease associations (from GenCC):

autosomal dominant Ehlers-Danlos syndrome, vascular type
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
Ehlers-Danlos syndrome, vascular type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
polymicrogyria with or without vascular-type Ehlers-Danlos syndrome
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

COL3A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000090.4

PP2

Missense variant in the COL3A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 495 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 4.0879 (above the threshold of 3.09). Trascript score misZ: 4.5995 (above the threshold of 3.09). GenCC associations: The gene is linked to Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, autosomal dominant Ehlers-Danlos syndrome, vascular type.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035955012).

BP6

Variant 2-188999354-G-A is Benign according to our data. Variant chr2-188999354-G-A is described in ClinVar as Benign. ClinVar VariationId is 17205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4 link	c.2092G>A	p.Ala698Thr	missense_variant	Exon 30 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL3A1	ENST00000304636.9 link	c.2092G>A	p.Ala698Thr	missense_variant	Exon 30 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2 link	c.1993G>A	p.Ala665Thr	missense_variant	Exon 29 of 50	1		ENSP00000415346.2
COL3A1	ENST00000713745.1 link	c.1939G>A	p.Ala647Thr	missense_variant	Exon 28 of 49			ENSP00000519049.1
COL3A1	ENST00000713744.1 link	c.2092G>A	p.Ala698Thr	missense_variant	Exon 30 of 49			ENSP00000519048.1

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32870

AN:

151956

Hom.:

3855

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.129

Gnomad AMR

AF:

0.232

Gnomad ASJ

AF:

0.301

Gnomad EAS

AF:

0.231

Gnomad SAS

AF:

0.303

Gnomad FIN

AF:

0.259

Gnomad MID

AF:

0.317

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.241

GnomAD2 exomes

AF:

0.249

AC:

54823

AN:

220080

AF XY:

0.258

show subpopulations

Gnomad AFR exome

AF:

0.116

Gnomad AMR exome

AF:

0.237

Gnomad ASJ exome

AF:

0.303

Gnomad EAS exome

AF:

0.224

Gnomad FIN exome

AF:

0.254

Gnomad NFE exome

AF:

0.253

Gnomad OTH exome

AF:

0.266

GnomAD4 exome

AF:

0.249

AC:

360083

AN:

1446434

Hom.:

45408

Cov.:

AF XY:

0.252

AC XY:

181090

AN XY:

718026

show subpopulations

African (AFR)

AF:

0.118

AC:

3919

AN:

33268

American (AMR)

AF:

0.242

AC:

10128

AN:

41840

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

7726

AN:

25776

East Asian (EAS)

AF:

0.249

AC:

9703

AN:

39000

South Asian (SAS)

AF:

0.309

AC:

26035

AN:

84392

European-Finnish (FIN)

AF:

0.257

AC:

13475

AN:

52484

Middle Eastern (MID)

AF:

0.330

AC:

1897

AN:

5744

European-Non Finnish (NFE)

AF:

0.247

AC:

272306

AN:

1104134

Other (OTH)

AF:

0.249

AC:

14894

AN:

59796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

15825

31650

47476

63301

79126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9306

18612

27918

37224

46530

<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:

0.216

AC:

32876

AN:

152074

Hom.:

3858

Cov.:

AF XY:

0.218

AC XY:

16217

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.121

AC:

5000

AN:

41482

American (AMR)

AF:

0.232

AC:

3549

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.301

AC:

1043

AN:

3470

East Asian (EAS)

AF:

0.231

AC:

1196

AN:

5170

South Asian (SAS)

AF:

0.303

AC:

1458

AN:

4814

European-Finnish (FIN)

AF:

0.259

AC:

2750

AN:

10598

Middle Eastern (MID)

AF:

0.328

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.253

AC:

17157

AN:

67948

Other (OTH)

AF:

0.241

AC:

510

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1282

2564

3846

5128

6410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<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:

0.240

Hom.:

12090

Bravo

AF:

0.210

TwinsUK

AF:

0.242

AC:

899

ALSPAC

AF:

0.244

AC:

940

ESP6500AA

AF:

0.134

AC:

592

ESP6500EA

AF:

0.255

AC:

2190

ExAC

AF:

0.231

AC:

27868

Asia WGS

AF:

0.235

AC:

817

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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

Dec 18, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

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

Nov 20, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ala698Thr in exon 30 of COL3A1: This variant is not expected to have clinical significance because it has been identified in 25% (2190/8600) of European Ameri can chromosomes and 13% (592/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1800255).

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Ehlers-Danlos syndrome, type 4

Benign:5

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 22, 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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Sep 23, 2022

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Nov 24, 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.

Mar 15, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

Benign:1

Nov 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: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

Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COLLAGEN TYPE III POLYMORPHISM

Benign:1

Oct 25, 1990

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;L

PhyloP100

0.11

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.20

Sift

Benign

0.23

T;T

Sift4G

Benign

0.18

T;T

Vest4

0.073

ClinPred

0.018

GERP RS

0.87

Varity_R

0.053

gMVP

0.14

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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