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:17
• 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

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 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 rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.2244T>C	p.Gly748Gly	synonymous_variant	Exon 32 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.2244T>C	p.Gly748Gly	synonymous_variant	Exon 32 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.2145T>C	p.Gly715Gly	synonymous_variant	Exon 31 of 50	1		ENSP00000415346.2

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

Gnomad4 AFR exome AF: 0.304 AC: 10162 AN: 33404

Gnomad4 AMR exome AF: 0.169 AC: 6840 AN: 40584

Gnomad4 ASJ exome AF: 0.343 AC: 8792 AN: 25666

Gnomad4 EAS exome AF: 0.0865 AC: 3391 AN: 39188

Gnomad4 SAS exome AF: 0.160 AC: 13193 AN: 82480

Gnomad4 FIN exome AF: 0.182 AC: 9489 AN: 52272

Gnomad4 NFE exome AF: 0.292 AC: 322380 AN: 1103204

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.299 AC: 0.299082 AN: 0.299082

Gnomad4 AMR AF: 0.252 AC: 0.252064 AN: 0.252064

Gnomad4 ASJ AF: 0.345 AC: 0.344758 AN: 0.344758

Gnomad4 EAS AF: 0.0748 AC: 0.0747971 AN: 0.0747971

Gnomad4 SAS AF: 0.158 AC: 0.158451 AN: 0.158451

Gnomad4 FIN AF: 0.166 AC: 0.166321 AN: 0.166321

Gnomad4 NFE AF: 0.292 AC: 0.291679 AN: 0.291679

Gnomad4 OTH AF: 0.302 AC: 0.302083 AN: 0.302083

Alfa AF: 0.288 Hom.: 18275

Bravo AF: 0.279

Asia WGS AF: 0.152 AC: 527 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 20, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Nov 20, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 05, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, type 4 Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Mar 15, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.60
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

Publications

LitVar

Other links and lift over

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