rs1801184

Variant names:

• chr2-188999856-T-C
• rs1801184
• NM_000090.4:c.2244T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000090.4(COL3A1):​c.2244T>C​(p.Gly748Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,594,368 control chromosomes in the GnomAD database, including 61,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5835 hom., cov: 31)
  • Exomes 𝑓: 0.27 (55824 hom.)
• Consequence: COL3A1 NM_000090.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -2.73
• Publications: 21 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• 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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-188999856-T-C is Benign according to our data. Variant chr2-188999856-T-C is described in ClinVar as Benign. ClinVar VariationId is 136853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 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.2244T>C	p.Gly748Gly	synonymous	Exon 32 of 51	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.2244T>C	p.Gly748Gly	synonymous	Exon 32 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.2145T>C	p.Gly715Gly	synonymous	Exon 31 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.2235T>C	p.Gly745Gly	synonymous	Exon 32 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41256 AN: 151874 Hom.: 5833 Cov.: 31

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.0752

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.301

GnomAD2 exomes AF: 0.234 AC: 51452 AN: 219808 AF XY: 0.235

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.0688

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.274

GnomAD4 exome AF: 0.272 AC: 392583 AN: 1442374 Hom.: 55824 Cov.: 35 AF XY: 0.270 AC XY: 192925 AN XY: 715132

African (AFR) AF: 0.304 AC: 10162 AN: 33404

American (AMR) AF: 0.169 AC: 6840 AN: 40584

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8792 AN: 25666

East Asian (EAS) AF: 0.0865 AC: 3391 AN: 39188

South Asian (SAS) AF: 0.160 AC: 13193 AN: 82480

European-Finnish (FIN) AF: 0.182 AC: 9489 AN: 52272

Middle Eastern (MID) AF: 0.380 AC: 2178 AN: 5734

European-Non Finnish (NFE) AF: 0.292 AC: 322380 AN: 1103204

Other (OTH) AF: 0.270 AC: 16158 AN: 59842

GnomAD4 genome AF: 0.272 AC: 41273 AN: 151994 Hom.: 5835 Cov.: 31 AF XY: 0.264 AC XY: 19649 AN XY: 74304

African (AFR) AF: 0.299 AC: 12376 AN: 41380

American (AMR) AF: 0.252 AC: 3846 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1197 AN: 3472

East Asian (EAS) AF: 0.0748 AC: 387 AN: 5174

South Asian (SAS) AF: 0.158 AC: 765 AN: 4828

European-Finnish (FIN) AF: 0.166 AC: 1762 AN: 10594

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.292 AC: 19826 AN: 67972

Other (OTH) AF: 0.302 AC: 638 AN: 2112

Alfa AF: 0.288 Hom.: 18275

Bravo AF: 0.279

Asia WGS AF: 0.152 AC: 527 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	Ehlers-Danlos syndrome, type 4 (4)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	2	not provided (2)
-	-	1	Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.60
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801184; hg19: chr2-189864582; COSMIC: COSV58593850; COSMIC: COSV58593850;