2-188997322-G-C

Position:

• chr2-188997322-G-C

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.1816-14G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,609,684 control chromosomes in the GnomAD database, including 17,440 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1961 hom., cov: 30)
  • Exomes 𝑓: 0.14 (15479 hom.)
• Consequence: COL3A1 NM_000090.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.685

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=-0.82).
• BP6: Variant 2-188997322-G-C is Benign according to our data. Variant chr2-188997322-G-C is described in ClinVar as [Benign]. Clinvar id is 136847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188997322-G-C is described in Lovd as [Benign].
• 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	Protein	UniProt
COL3A1	NM_000090.4	c.1816-14G>C		intron_variant		ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1816-14G>C		intron_variant		1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.1717-14G>C		intron_variant		1		ENSP00000415346.2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23640 AN: 151774 Hom.: 1960 Cov.: 30

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.00426

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0907

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.157

GnomAD3 exomes AF: 0.123 AC: 30889 AN: 251198 Hom.: 2222 AF XY: 0.125 AC XY: 16914 AN XY: 135774

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0785

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.00130

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.0950

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.140 AC: 203785 AN: 1457792 Hom.: 15479 Cov.: 34 AF XY: 0.139 AC XY: 100956 AN XY: 725422

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.0824

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.000982

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.0984

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.156 AC: 23657 AN: 151892 Hom.: 1961 Cov.: 30 AF XY: 0.153 AC XY: 11345 AN XY: 74234

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.00427

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0907

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.159

Alfa AF: 0.146 Hom.: 297

Bravo AF: 0.161

Asia WGS AF: 0.0990 AC: 343 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2013	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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	1816-14G>C in intron 25 of COL3A1: This variant is not expected to have clinical significance because it has been identified in 20.2% (892/4406) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs7579815). -
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	-	- -

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: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	-0.82
CADD	Benign	2.0
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: rs7579815; hg19: chr2-189862048;