rs7579903

chr2-188997371-G-A

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.1851G>A(p.Gln617=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,608,662 control chromosomes in the GnomAD database, including 17,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. QGP617QA) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.16 (1961 hom., cov: 30)
  • Exomes 𝑓: 0.14 (15382 hom.)
• Consequence: COL3A1 NM_000090.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.278

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=-0.74).
• BP6: Variant 2-188997371-G-A is Benign according to our data. Variant chr2-188997371-G-A is described in ClinVar as [Benign]. Clinvar id is 136848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188997371-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.278 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.1851G>A	p.Gln617=	synonymous_variant	26/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.1851G>A	p.Gln617=	synonymous_variant	26/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.1752G>A	p.Gln584=	synonymous_variant	25/50	1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23621 AN: 151906 Hom.: 1960 Cov.: 30

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.123 AC: 30763 AN: 251060 Hom.: 2199 AF XY: 0.124 AC XY: 16850 AN XY: 135768

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.0783

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0948

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.139 AC: 202690 AN: 1456638 Hom.: 15382 Cov.: 34 AF XY: 0.138 AC XY: 100368 AN XY: 724838

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.0823

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.000957

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0983

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.155 AC: 23638 AN: 152024 Hom.: 1961 Cov.: 30 AF XY: 0.153 AC XY: 11333 AN XY: 74310

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0896

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.158

Alfa AF: 0.149 Hom.: 2914

Bravo AF: 0.160

Asia WGS AF: 0.0980 AC: 340 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.152

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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.Gln617Gln in exon 26 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 15% (1263/8600) of European American chromosomes and 20% (877/4406) of African American chromoso mes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; db SNP rs7579903). -
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, 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. -

Ehlers-Danlos syndrome, type 4 Benign:5

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
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, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Genome-Nilou Lab	Jul 22, 2021	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2018	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	4.8
Dann	Benign	0.63

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: rs7579903; hg19: chr2-189862097;