rs1801184

Positions:

• chr2-188999856-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000090.4(COL3A1):​c.2244T>C​(p.Gly748=) 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:16
• Conservation: PhyloP100: -2.73

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 -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 id is 136853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188999856-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.2244T>C	p.Gly748=	synonymous_variant	32/51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.2244T>C	p.Gly748=	synonymous_variant	32/51	1	NM_000090.4	ENSP00000304408	P1
COL3A1	ENST00000450867.2	c.2145T>C	p.Gly715=	synonymous_variant	31/50	1		ENSP00000415346

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

GnomAD3 exomes AF: 0.234 AC: 51452 AN: 219808 Hom.: 6705 AF XY: 0.235 AC XY: 27593 AN XY: 117192

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 SAS exome AF: 0.157

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

Gnomad4 AFR exome AF: 0.304

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.343

Gnomad4 EAS exome AF: 0.0865

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.182

Gnomad4 NFE exome AF: 0.292

Gnomad4 OTH exome AF: 0.270

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

Gnomad4 AFR AF: 0.299

Gnomad4 AMR AF: 0.252

Gnomad4 ASJ AF: 0.345

Gnomad4 EAS AF: 0.0748

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.302

Alfa AF: 0.298 Hom.: 8283

Bravo AF: 0.279

Asia WGS AF: 0.152 AC: 527 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2019	Variant summary: COL3A1 c.2244T>C alters a non-conserved nucleotide resulting in a synonymous change. The variant allele was found at a frequency of 0.23 in 219808 control chromosomes in the gnomAD database, including 6705 homozygotes, strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2244T>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 20, 2014	p.Gly748Gly in exon 32 of COL3A1: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 29% (2489/8596) of European American chromosomes and 28% (1217/4406) of African American chromos omes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; d bSNP rs1801184). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 05, 2016	- -

Ehlers-Danlos syndrome, type 4 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 24, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
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	0.60

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

Publications

LitVar

Other links and lift over

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