rs3765161

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000090.4(COL3A1):c.2608-50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 1,573,600 control chromosomes in the GnomAD database, including 5,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.12 ( 2459 hom., cov: 32)

Exomes 𝑓: 0.040 ( 2790 hom. )

Consequence

COL3A1
NM_000090.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.57

Publications

3 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 -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 2-189003684-C-T is Benign according to our data. Variant chr2-189003684-C-T is described in ClinVar as Benign. ClinVar VariationId is 254964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4 link	c.2608-50C>T		intron_variant	Intron 37 of 50	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.2608-50C>T		intron_variant	Intron 37 of 50	1	NM_000090.4	ENSP00000304408.4		P02461-1

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18115

AN:

151954

Hom.:

2438

Cov.:

show subpopulations

Gnomad AFR

AF:

0.334

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0569

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.0908

Gnomad SAS

AF:

0.0457

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0321

Gnomad OTH

AF:

0.101

GnomAD2 exomes

AF:

0.0587

AC:

14734

AN:

250928

AF XY:

0.0534

show subpopulations

Gnomad AFR exome

AF:

0.342

Gnomad AMR exome

AF:

0.0346

Gnomad ASJ exome

AF:

0.0247

Gnomad EAS exome

AF:

0.0950

Gnomad FIN exome

AF:

0.0244

Gnomad NFE exome

AF:

0.0334

Gnomad OTH exome

AF:

0.0510

GnomAD4 exome

AF:

0.0395

AC:

56201

AN:

1421528

Hom.:

2790

Cov.:

AF XY:

0.0387

AC XY:

27498

AN XY:

709814

show subpopulations

African (AFR)

AF:

0.341

AC:

11105

AN:

32592

American (AMR)

AF:

0.0370

AC:

1651

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.0241

AC:

624

AN:

25874

East Asian (EAS)

AF:

0.0838

AC:

3310

AN:

39484

South Asian (SAS)

AF:

0.0435

AC:

3720

AN:

85448

European-Finnish (FIN)

AF:

0.0248

AC:

1321

AN:

53372

Middle Eastern (MID)

AF:

0.0540

AC:

308

AN:

5706

European-Non Finnish (NFE)

AF:

0.0287

AC:

30904

AN:

1075344

Other (OTH)

AF:

0.0552

AC:

3258

AN:

59062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

2781

5562

8344

11125

13906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1280

2560

3840

5120

6400

<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:

0.120

AC:

18185

AN:

152072

Hom.:

2459

Cov.:

AF XY:

0.117

AC XY:

8696

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.335

AC:

13868

AN:

41454

American (AMR)

AF:

0.0567

AC:

867

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

108

AN:

3472

East Asian (EAS)

AF:

0.0906

AC:

467

AN:

5156

South Asian (SAS)

AF:

0.0459

AC:

221

AN:

4810

European-Finnish (FIN)

AF:

0.0214

AC:

227

AN:

10596

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0321

AC:

2184

AN:

67992

Other (OTH)

AF:

0.100

AC:

211

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

668

1336

2005

2673

3341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

174

348

522

696

870

<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:

0.0733

Hom.:

404

Bravo

AF:

0.131

Asia WGS

AF:

0.0920

AC:

319

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 18, 2018

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.068

(source)

DANN

Benign

0.43

PhyloP100

-1.6

BranchPoint Hunter

0.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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