rs3765161

Variant names:

• chr2-189003684-C-T
• rs3765161
• NM_000090.4:c.2608-50C>T

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.2608-50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 1,573,600 control chromosomes in the GnomAD database, including 5,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.12 (2459 hom., cov: 32)
  • Exomes 𝑓: 0.040 (2790 hom.)
• Consequence: COL3A1 NM_000090.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.57
• 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: 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-189003684-C-T is Benign according to our data. Variant chr2-189003684-C-T is described in ClinVar as Benign. ClinVar VariationId is 254964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 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.2608-50C>T		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.2608-50C>T		intron	N/A	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.2509-50C>T		intron	N/A	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.2599-50C>T		intron	N/A	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18115 AN: 151954 Hom.: 2438 Cov.: 32

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0569

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.0908

Gnomad SAS AF: 0.0457

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0321

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.0587 AC: 14734 AN: 250928 AF XY: 0.0534

Gnomad AFR exome AF: 0.342

Gnomad AMR exome AF: 0.0346

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.0950

Gnomad FIN exome AF: 0.0244

Gnomad NFE exome AF: 0.0334

Gnomad OTH exome AF: 0.0510

GnomAD4 exome AF: 0.0395 AC: 56201 AN: 1421528 Hom.: 2790 Cov.: 27 AF XY: 0.0387 AC XY: 27498 AN XY: 709814

African (AFR) AF: 0.341 AC: 11105 AN: 32592

American (AMR) AF: 0.0370 AC: 1651 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 624 AN: 25874

East Asian (EAS) AF: 0.0838 AC: 3310 AN: 39484

South Asian (SAS) AF: 0.0435 AC: 3720 AN: 85448

European-Finnish (FIN) AF: 0.0248 AC: 1321 AN: 53372

Middle Eastern (MID) AF: 0.0540 AC: 308 AN: 5706

European-Non Finnish (NFE) AF: 0.0287 AC: 30904 AN: 1075344

Other (OTH) AF: 0.0552 AC: 3258 AN: 59062

GnomAD4 genome AF: 0.120 AC: 18185 AN: 152072 Hom.: 2459 Cov.: 32 AF XY: 0.117 AC XY: 8696 AN XY: 74338

African (AFR) AF: 0.335 AC: 13868 AN: 41454

American (AMR) AF: 0.0567 AC: 867 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3472

East Asian (EAS) AF: 0.0906 AC: 467 AN: 5156

South Asian (SAS) AF: 0.0459 AC: 221 AN: 4810

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10596

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0321 AC: 2184 AN: 67992

Other (OTH) AF: 0.100 AC: 211 AN: 2108

Alfa AF: 0.0733 Hom.: 404

Bravo AF: 0.131

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.068
DANN	Benign	0.43
PhyloP100		-1.6
BranchPoint Hunter		0.0
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: rs3765161; hg19: chr2-189868410; COSMIC: COSV107352710; COSMIC: COSV107352710;