chr2-188994347-T-A

Variant names:

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000090.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	NM_000090.4	MANE Select	c.1293+15T>A		intron	N/A	NP_000081.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	ENST00000304636.9	TSL:1 MANE Select	c.1293+15T>A		intron	N/A	ENSP00000304408.4
	COL3A1	ENST00000450867.2	TSL:1	c.1194+15T>A		intron	N/A	ENSP00000415346.2
	COL3A1	ENST00000879201.1		c.1284+15T>A		intron	N/A	ENSP00000549260.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Ehlers-Danlos syndrome, type 4 (2)
-	-	1	Familial aortopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;