rs1800255

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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:20

Conservation

PhyloP100: 0.112

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL3A1. . Gene score misZ 4.0879 (greater than the threshold 3.09). Trascript score misZ 4.5995 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, vascular type, autosomal dominant Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome.

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 id is 17205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188999354-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4 linkuse as main transcript	c.2092G>A	p.Ala698Thr	missense_variant	30/51	ENST00000304636.9	NP_000081.2	P02461-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9 linkuse as main transcript	c.2092G>A	p.Ala698Thr	missense_variant	30/51	1	NM_000090.4	ENSP00000304408.4		P02461-1
COL3A1	ENST00000450867.2 linkuse as main transcript	c.1993G>A	p.Ala665Thr	missense_variant	29/50	1		ENSP00000415346.2		H7C435

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

GnomAD3 exomes

AF:

0.249

AC:

54823

AN:

220080

Hom.:

6896

AF XY:

0.258

AC XY:

30613

AN XY:

118804

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 SAS exome

AF:

0.305

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

Gnomad4 AFR exome

AF:

0.118

Gnomad4 AMR exome

AF:

0.242

Gnomad4 ASJ exome

AF:

0.300

Gnomad4 EAS exome

AF:

0.249

Gnomad4 SAS exome

AF:

0.309

Gnomad4 FIN exome

AF:

0.257

Gnomad4 NFE exome

AF:

0.247

Gnomad4 OTH exome

AF:

0.249

GnomAD4 genome

AF:

0.216

AC:

32876

AN:

152074

Hom.:

3858

Cov.:

AF XY:

0.218

AC XY:

16217

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.121

Gnomad4 AMR

AF:

0.232

Gnomad4 ASJ

AF:

0.301

Gnomad4 EAS

AF:

0.231

Gnomad4 SAS

AF:

0.303

Gnomad4 FIN

AF:

0.259

Gnomad4 NFE

AF:

0.253

Gnomad4 OTH

AF:

0.241

Alfa

AF:

0.248

Hom.:

8450

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:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 20, 2014	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). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2012	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. -

Ehlers-Danlos syndrome, type 4

Benign:5

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 24, 2014	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 10, 2021

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2022

- -

Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

COLLAGEN TYPE III POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 25, 1990

- -

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

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

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

Polyphen

0.0

B;.

Vest4

0.073

MPC

0.61

ClinPred

0.018

GERP RS

0.87

Varity_R

0.053

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over