rs2271683

Positions:

chr2-189009011-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000304636.9(COL3A1):c.3613A>G(p.Ile1205Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,168 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I1205I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0024 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 111 hom. )

Consequence

COL3A1
ENST00000304636.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.91

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=0.0019847155).

BP6

Variant 2-189009011-A-G is Benign according to our data. Variant chr2-189009011-A-G is described in ClinVar as [Benign]. Clinvar id is 136856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189009011-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.054 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.3613A>G	p.Ile1205Val	missense_variant	48/51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9 linkuse as main transcript	c.3613A>G	p.Ile1205Val	missense_variant	48/51	1	NM_000090.4	ENSP00000304408	P1	P02461-1
COL3A1	ENST00000450867.2 linkuse as main transcript	c.3514A>G	p.Ile1172Val	missense_variant	47/50	1		ENSP00000415346
COL3A1	ENST00000487010.1 linkuse as main transcript	n.710A>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

362

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0595

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00443

AC:

1114

AN:

251388

Hom.:

AF XY:

0.00398

AC XY:

541

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0529

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00282

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00247

AC:

3612

AN:

1461892

Hom.:

111

Cov.:

AF XY:

0.00238

AC XY:

1734

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0755

Gnomad4 SAS exome

AF:

0.00166

Gnomad4 FIN exome

AF:

0.00273

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.00298

GnomAD4 genome

AF:

0.00237

AC:

361

AN:

152276

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

208

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0595

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00193

Hom.:

Bravo

AF:

0.00247

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00447

AC:

543

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 05, 2015	p.Ile1205Val in exon 48 of COL3A1: This variant is not expected to have clinical significance because it has been identified in 5.6% (482/8650) of East Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs2271683). -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 29, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 30, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 18, 2016	- -

Ehlers-Danlos syndrome, type 4

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.039

DANN

Benign

0.22

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.32

N;N

REVEL

Benign

0.22

Sift

Benign

0.54

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.0

B;.

Vest4

0.14

MVP

0.34

MPC

0.17

ClinPred

0.0018

GERP RS

-11

Varity_R

0.025

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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