rs1516446

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000090.4(COL3A1):c.4059T>G(p.His1353Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,614,158 control chromosomes in the GnomAD database, including 805,640 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 (★★).

Frequency

Genomes: 𝑓 1.0 ( 75488 hom., cov: 32)

Exomes 𝑓: 1.0 ( 730152 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.72

Publications

36 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 -19 ACMG points.

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=8.1083687E-7).

BP6

Variant 2-189010695-T-G is Benign according to our data. Variant chr2-189010695-T-G is described in ClinVar as Benign. ClinVar VariationId is 226540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4 link	c.4059T>G	p.His1353Gln	missense_variant	Exon 50 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9 link	c.4059T>G	p.His1353Gln	missense_variant	Exon 50 of 51	1	NM_000090.4	ENSP00000304408.4

Frequencies

GnomAD3 genomes

AF:

0.996

AC:

151524

AN:

152196

Hom.:

75430

Cov.:

show subpopulations

Gnomad AFR

AF:

0.985

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.999

Gnomad ASJ

AF:

0.997

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.998

GnomAD2 exomes

AF:

0.999

AC:

250991

AN:

251310

AF XY:

0.999

show subpopulations

Gnomad AFR exome

AF:

0.985

Gnomad AMR exome

AF:

0.999

Gnomad ASJ exome

AF:

0.996

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.999

GnomAD4 exome

AF:

0.999

AC:

1461064

AN:

1461844

Hom.:

730152

Cov.:

AF XY:

1.00

AC XY:

726861

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.985

AC:

32972

AN:

33480

American (AMR)

AF:

0.999

AC:

44681

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

26039

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39696

AN:

39696

South Asian (SAS)

AF:

1.00

AC:

86253

AN:

86256

European-Finnish (FIN)

AF:

1.00

AC:

53418

AN:

53418

Middle Eastern (MID)

AF:

0.999

AC:

5760

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111934

AN:

1111970

Other (OTH)

AF:

0.999

AC:

60311

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21672

43344

65016

86688

108360

<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:

0.996

AC:

151641

AN:

152314

Hom.:

75488

Cov.:

AF XY:

0.996

AC XY:

74169

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.985

AC:

40920

AN:

41550

American (AMR)

AF:

0.999

AC:

15278

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.997

AC:

3463

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5188

AN:

5188

South Asian (SAS)

AF:

1.00

AC:

4824

AN:

4824

European-Finnish (FIN)

AF:

1.00

AC:

10618

AN:

10618

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68034

AN:

68040

Other (OTH)

AF:

0.998

AC:

2111

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<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:

0.998

Hom.:

199474

Bravo

AF:

0.995

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.985

AC:

4340

ESP6500EA

AF:

1.00

AC:

8600

ExAC

AF:

0.999

AC:

121231

Asia WGS

AF:

0.999

AC:

3475

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 02, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is a RefSeq error. The reference base (c.4059T) is the minor allele. This a llele (T) has been identified in 1.5% (66/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1516446) and thus meets criteria to be classified as benign. -

Jan 05, 2017

Eurofins Ntd Llc (ga)

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

- -

Ehlers-Danlos syndrome, type 4

Benign:4

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 03, 2024

All of Us Research Program, National Institutes of Health

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

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2014

Ambry Genetics

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

8.1e-7

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-3.7

N;.

PhyloP100

1.7

PrimateAI

Uncertain

0.58

PROVEAN

Benign

4.7

N;N

REVEL

Benign

0.20

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.19

MutPred

0.73

Loss of helix (P = 0.028);.;

MPC

0.21

ClinPred

0.00099

GERP RS

1.4

Varity_R

0.068

gMVP

0.51

Mutation Taster

=93/7

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