rs149722210

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS1

The NM_000090.4(COL3A1):c.3133G>A(p.Ala1045Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1045V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:16

Conservation

PhyloP100: 1.47

Publications

9 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:

ENSG00000295704 (HGNC:):

ENSG00000295704 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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=0.014062673).

BP6

Variant 2-189006384-G-A is Benign according to our data. Variant chr2-189006384-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197477.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000368 (56/152244) while in subpopulation EAS AF = 0.00618 (32/5174). AF 95% confidence interval is 0.0045. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4 link	c.3133G>A	p.Ala1045Thr	missense_variant	Exon 43 of 51	ENST00000304636.9	NP_000081.2	P02461-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9 link	c.3133G>A	p.Ala1045Thr	missense_variant	Exon 43 of 51	1	NM_000090.4	ENSP00000304408.4		P02461-1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00617

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000573

AC:

144

AN:

251364

AF XY:

0.000574

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00533

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000276

AC:

403

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

223

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00486

AC:

193

AN:

39700

South Asian (SAS)

AF:

0.000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000755

AC:

AN:

1112006

Other (OTH)

AF:

0.000944

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000368

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41542

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00618

AC:

AN:

5174

South Asian (SAS)

AF:

0.00104

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000218

Hom.:

Bravo

AF:

0.000510

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000585

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.5% (46/8636) East Asian; ClinVar: 1 VUS, 1 LB; Path for nonsense at same codon -

Apr 24, 2015

Eurofins Ntd Llc (ga)

Significance:Likely 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

- -

Jan 06, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Nov 25, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22001912, 25834947, 30115950, 27888582, 32123317) -

Jun 12, 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 COL3A1 c.3133G>A (p.Ala1045Thr) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome. However, these predictions have yet to be functionally assessed. This variant was found in 71/121484 control chromosomes at a frequency of 0.0005844, which is approximately 468 times the estimated maximal expected allele frequency of a pathogenic COL3A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, type 4

Benign:4

Jun 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Dec 01, 2015

CSER _CC_NCGL, University of Washington

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 07, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Aug 11, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 13, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Oct 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Feb 23, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Connective tissue disorder

Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.1

PhyloP100

1.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.34

Sift

Benign

0.086

Sift4G

Benign

0.26

Polyphen

0.99

Vest4

0.42

MVP

0.82

MPC

1.2

ClinPred

0.034

GERP RS

2.3

Varity_R

0.045

gMVP

0.18

Mutation Taster

=87/13

polymorphism

(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