chr2-188998663-C-T

Position:

• chr2-188998663-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000090.4(COL3A1):​c.1978-11C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,608,644 control chromosomes in the GnomAD database, including 53,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4504 hom., cov: 32)
  • Exomes 𝑓: 0.26 (48561 hom.)
• Consequence: COL3A1 NM_000090.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002065
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.782

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-188998663-C-T is Benign according to our data. Variant chr2-188998663-C-T is described in ClinVar as [Benign]. Clinvar id is 136851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188998663-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.1978-11C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1978-11C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000090.4	ENSP00000304408	P1
COL3A1	ENST00000450867.2	c.1879-11C>T		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000415346

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36454 AN: 151882 Hom.: 4498 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.263 AC: 66004 AN: 250800 Hom.: 8797 AF XY: 0.272 AC XY: 36875 AN XY: 135558

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.244

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.226

Gnomad SAS exome AF: 0.342

Gnomad FIN exome AF: 0.256

Gnomad NFE exome AF: 0.260

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.255 AC: 372154 AN: 1456646 Hom.: 48561 Cov.: 32 AF XY: 0.260 AC XY: 188332 AN XY: 724896

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.314

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.343

Gnomad4 FIN exome AF: 0.259

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.240 AC: 36469 AN: 151998 Hom.: 4504 Cov.: 32 AF XY: 0.242 AC XY: 17989 AN XY: 74292

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.336

Gnomad4 FIN AF: 0.262

Gnomad4 NFE AF: 0.257

Gnomad4 OTH AF: 0.261

Alfa AF: 0.258 Hom.: 1125

Bravo AF: 0.235

Asia WGS AF: 0.249 AC: 865 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	1978-11C>T in intron 28 of COL3A1: This variant is not expected to have clinical significance because it has been identified in 26.1% (2242/8600) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs13306272). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Ehlers-Danlos syndrome, type 4 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs13306272; hg19: chr2-189863389;