chr2-189001616-AC-A

Variant names:

• chr2-189001616-AC-A
• rs3215251
• NM_000090.4:c.2391+28delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000090.4(COL3A1):​c.2391+28delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,613,292 control chromosomes in the GnomAD database, including 5,399 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2610 hom., cov: 30)
  • Exomes 𝑓: 0.033 (2789 hom.)
• Consequence: COL3A1 NM_000090.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.96
• Publications: 4 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 -16 ACMG points.

• BP6: Variant 2-189001616-AC-A is Benign according to our data. Variant chr2-189001616-AC-A is described in ClinVar as Benign. ClinVar VariationId is 254963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.2391+28delC		intron_variant	Intron 34 of 50	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.2391+28delC		intron_variant	Intron 34 of 50	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.2292+28delC		intron_variant	Intron 33 of 49	1		ENSP00000415346.2
COL3A1	ENST00000713745.1	c.2238+28delC		intron_variant	Intron 32 of 48			ENSP00000519049.1
COL3A1	ENST00000713744.1	c.2391+28delC		intron_variant	Intron 34 of 48			ENSP00000519048.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17995 AN: 151972 Hom.: 2589 Cov.: 30

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0548

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.0881

Gnomad SAS AF: 0.0456

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.0545 AC: 13699 AN: 251350 AF XY: 0.0488

Gnomad AFR exome AF: 0.359

Gnomad AMR exome AF: 0.0322

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.0933

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.0239

Gnomad OTH exome AF: 0.0467

GnomAD4 exome AF: 0.0327 AC: 47798 AN: 1461202 Hom.: 2789 Cov.: 33 AF XY: 0.0322 AC XY: 23381 AN XY: 726904

African (AFR) AF: 0.358 AC: 11972 AN: 33450

American (AMR) AF: 0.0355 AC: 1586 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0235 AC: 615 AN: 26132

East Asian (EAS) AF: 0.0827 AC: 3281 AN: 39692

South Asian (SAS) AF: 0.0447 AC: 3857 AN: 86248

European-Finnish (FIN) AF: 0.0164 AC: 875 AN: 53410

Middle Eastern (MID) AF: 0.0530 AC: 304 AN: 5736

European-Non Finnish (NFE) AF: 0.0200 AC: 22191 AN: 1111438

Other (OTH) AF: 0.0516 AC: 3117 AN: 60372

GnomAD4 genome AF: 0.119 AC: 18061 AN: 152090 Hom.: 2610 Cov.: 30 AF XY: 0.115 AC XY: 8579 AN XY: 74388

African (AFR) AF: 0.350 AC: 14502 AN: 41448

American (AMR) AF: 0.0546 AC: 834 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0302 AC: 105 AN: 3472

East Asian (EAS) AF: 0.0880 AC: 454 AN: 5162

South Asian (SAS) AF: 0.0459 AC: 221 AN: 4820

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0229 AC: 1555 AN: 67998

Other (OTH) AF: 0.102 AC: 214 AN: 2106

Alfa AF: 0.0112 Hom.: 42

Bravo AF: 0.132

Asia WGS AF: 0.0930 AC: 325 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3215251; hg19: chr2-189866342; COSMIC: COSV107352711; COSMIC: COSV107352711;