rs2271679

Variant names:

• chr2-188994347-T-A
• rs2271679
• NM_000090.4:c.1293+15T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-188994347-T-A
• chr2-188994347-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000090.4(COL3A1):​c.1293+15T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,613,044 control chromosomes in the GnomAD database, including 6,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2992 hom., cov: 32)
  • Exomes 𝑓: 0.033 (3172 hom.)
• Consequence: COL3A1 NM_000090.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.26
• Publications: 3 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-188994347-T-A is Benign according to our data. Variant chr2-188994347-T-A is described in ClinVar as Benign. ClinVar VariationId is 35961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.1293+15T>A		intron_variant	Intron 18 of 50	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1293+15T>A		intron_variant	Intron 18 of 50	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.1194+15T>A		intron_variant	Intron 17 of 49	1		ENSP00000415346.2
COL3A1	ENST00000713745.1	c.1293+15T>A		intron_variant	Intron 18 of 48			ENSP00000519049.1
COL3A1	ENST00000713744.1	c.1293+15T>A		intron_variant	Intron 18 of 48			ENSP00000519048.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19163 AN: 152030 Hom.: 2971 Cov.: 32

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0593

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.0883

Gnomad SAS AF: 0.0468

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.0565 AC: 14176 AN: 250700 AF XY: 0.0503

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.0331

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.0927

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.0240

Gnomad OTH exome AF: 0.0478

GnomAD4 exome AF: 0.0335 AC: 48920 AN: 1460896 Hom.: 3172 Cov.: 32 AF XY: 0.0329 AC XY: 23885 AN XY: 726740

African (AFR) AF: 0.385 AC: 12888 AN: 33436

American (AMR) AF: 0.0368 AC: 1647 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0235 AC: 615 AN: 26134

East Asian (EAS) AF: 0.0823 AC: 3267 AN: 39690

South Asian (SAS) AF: 0.0455 AC: 3922 AN: 86222

European-Finnish (FIN) AF: 0.0164 AC: 873 AN: 53386

Middle Eastern (MID) AF: 0.0557 AC: 296 AN: 5310

European-Non Finnish (NFE) AF: 0.0200 AC: 22208 AN: 1111694

Other (OTH) AF: 0.0531 AC: 3204 AN: 60306

GnomAD4 genome AF: 0.126 AC: 19229 AN: 152148 Hom.: 2992 Cov.: 32 AF XY: 0.122 AC XY: 9101 AN XY: 74398

African (AFR) AF: 0.376 AC: 15586 AN: 41444

American (AMR) AF: 0.0591 AC: 903 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 105 AN: 3466

East Asian (EAS) AF: 0.0881 AC: 457 AN: 5186

South Asian (SAS) AF: 0.0471 AC: 227 AN: 4820

European-Finnish (FIN) AF: 0.0134 AC: 142 AN: 10612

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0228 AC: 1550 AN: 68014

Other (OTH) AF: 0.108 AC: 227 AN: 2110

Alfa AF: 0.0340 Hom.: 83

Bravo AF: 0.142

Asia WGS AF: 0.0940 AC: 327 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Apr 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1293+15T>A in intron 18 of COL3A1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence. It has been identified in 37.0% (1631/4404) of African American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs2271679). -

-

PreventionGenetics, part of Exact Sciences

Significance: 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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 05, 2012

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. -

Ehlers-Danlos syndrome, type 4 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 aortopathy Benign:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.27
DANN	Benign	0.67
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2271679; hg19: chr2-189859073; COSMIC: COSV58584461; COSMIC: COSV58584461;