rs1800255

chr2-188999354-G-Achr2-188999354-G-Cchr2-188999354-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000090.4(COL3A1):c.2092G>A(p.Ala698Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,598,508 control chromosomes in the GnomAD database, including 49,266 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3858 hom., cov: 32)
  • Exomes 𝑓: 0.25 (45408 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.112

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 -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000090.4
• PP2: Missense variant where missense usually causes diseases, COL3A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035955012).
• BP6: Variant 2-188999354-G-A is Benign according to our data. Variant chr2-188999354-G-A is described in ClinVar as [Benign]. Clinvar id is 17205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188999354-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.2092G>A	p.Ala698Thr	missense_variant	30/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.2092G>A	p.Ala698Thr	missense_variant	30/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.1993G>A	p.Ala665Thr	missense_variant	29/50	1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32870 AN: 151956 Hom.: 3855 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.317

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.241

GnomAD3 exomes AF: 0.249 AC: 54823 AN: 220080 Hom.: 6896 AF XY: 0.258 AC XY: 30613 AN XY: 118804

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.224

Gnomad SAS exome AF: 0.305

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.249 AC: 360083 AN: 1446434 Hom.: 45408 Cov.: 37 AF XY: 0.252 AC XY: 181090 AN XY: 718026

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.257

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.249

GnomAD4 genome AF: 0.216 AC: 32876 AN: 152074 Hom.: 3858 Cov.: 32 AF XY: 0.218 AC XY: 16217 AN XY: 74342

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.232

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.253

Gnomad4 OTH AF: 0.241

Alfa AF: 0.248 Hom.: 8450

Bravo AF: 0.210

TwinsUK AF: 0.242 AC: 899

ALSPAC AF: 0.244 AC: 940

ESP6500AA AF: 0.134 AC: 592

ESP6500EA AF: 0.255 AC: 2190

ExAC AF: 0.231 AC: 27868

Asia WGS AF: 0.235 AC: 817 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2014	- -
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	Nov 20, 2014	p.Ala698Thr in exon 30 of COL3A1: This variant is not expected to have clinical significance because it has been identified in 25% (2190/8600) of European Ameri can chromosomes and 13% (592/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1800255). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	-	- -

Ehlers-Danlos syndrome, type 4 Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

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	- -

Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 10, 2021

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

COLLAGEN TYPE III POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Oct 25, 1990

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.71	P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.20
Sift	Benign	0.23	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0	B;.
Vest4		0.073
MPC		0.61
ClinPred		0.018	T
GERP RS		0.87
Varity_R		0.053
gMVP		0.14

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: rs1800255; hg19: chr2-189864080; COSMIC: COSV58587972; COSMIC: COSV58587972;