rs28413125

Variant names:

• chr2-188997236-A-G
• rs28413125
• NM_000090.4:c.1815+18A>G

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.1815+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,613,690 control chromosomes in the GnomAD database, including 2,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (1307 hom., cov: 30)
  • Exomes 𝑓: 0.013 (1274 hom.)
• Consequence: COL3A1 NM_000090.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.632
• Publications: 10 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-188997236-A-G is Benign according to our data. Variant chr2-188997236-A-G is described in ClinVar as Benign. ClinVar VariationId is 136846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	NM_000090.4	MANE Select	c.1815+18A>G		intron	N/A	NP_000081.2	P02461-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	ENST00000304636.9	TSL:1 MANE Select	c.1815+18A>G		intron	N/A	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.1716+18A>G		intron	N/A	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.1806+18A>G		intron	N/A	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.0762 AC: 11560 AN: 151760 Hom.: 1304 Cov.: 30

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0816

Gnomad SAS AF: 0.0318

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.0679

GnomAD2 exomes AF: 0.0311 AC: 7814 AN: 251390 AF XY: 0.0273

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.0863

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0132 AC: 19299 AN: 1461812 Hom.: 1274 Cov.: 33 AF XY: 0.0129 AC XY: 9410 AN XY: 727208

African (AFR) AF: 0.250 AC: 8354 AN: 33442

American (AMR) AF: 0.0188 AC: 840 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00275 AC: 72 AN: 26136

East Asian (EAS) AF: 0.0766 AC: 3040 AN: 39698

South Asian (SAS) AF: 0.0313 AC: 2701 AN: 86256

European-Finnish (FIN) AF: 0.00234 AC: 125 AN: 53414

Middle Eastern (MID) AF: 0.0229 AC: 132 AN: 5768

European-Non Finnish (NFE) AF: 0.00216 AC: 2401 AN: 1111978

Other (OTH) AF: 0.0271 AC: 1634 AN: 60396

GnomAD4 genome AF: 0.0763 AC: 11590 AN: 151878 Hom.: 1307 Cov.: 30 AF XY: 0.0748 AC XY: 5554 AN XY: 74248

African (AFR) AF: 0.245 AC: 10133 AN: 41304

American (AMR) AF: 0.0310 AC: 474 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3466

East Asian (EAS) AF: 0.0814 AC: 420 AN: 5160

South Asian (SAS) AF: 0.0323 AC: 155 AN: 4800

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10594

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 67972

Other (OTH) AF: 0.0672 AC: 142 AN: 2114

Alfa AF: 0.0507 Hom.: 436

Bravo AF: 0.0869

Asia WGS AF: 0.0740 AC: 257 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.12
DANN	Benign	0.54
PhyloP100		-0.63
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: rs28413125; hg19: chr2-189861962; COSMIC: COSV58584466; COSMIC: COSV58584466;