rs28413125

chr2-188997236-A-G

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.1815+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,613,690 control chromosomes in the GnomAD database, including 2,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (1307 hom., cov: 30)
  • Exomes 𝑓: 0.013 (1274 hom.)
• Consequence: COL3A1 NM_000090.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.632

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=-0.83).
• BP6: Variant 2-188997236-A-G is Benign according to our data. Variant chr2-188997236-A-G is described in ClinVar as [Benign]. Clinvar id is 136846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188997236-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.1815+18A>G		intron_variant		ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.1815+18A>G		intron_variant		1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.1716+18A>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0762 AC: 11560 AN: 151760 Hom.: 1304 Cov.: 30

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0816

Gnomad SAS AF: 0.0318

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.0679

GnomAD3 exomes AF: 0.0311 AC: 7814 AN: 251390 Hom.: 615 AF XY: 0.0273 AC XY: 3705 AN XY: 135878

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.0863

Gnomad SAS exome AF: 0.0328

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0132 AC: 19299 AN: 1461812 Hom.: 1274 Cov.: 33 AF XY: 0.0129 AC XY: 9410 AN XY: 727208

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.0188

Gnomad4 ASJ exome AF: 0.00275

Gnomad4 EAS exome AF: 0.0766

Gnomad4 SAS exome AF: 0.0313

Gnomad4 FIN exome AF: 0.00234

Gnomad4 NFE exome AF: 0.00216

Gnomad4 OTH exome AF: 0.0271

GnomAD4 genome AF: 0.0763 AC: 11590 AN: 151878 Hom.: 1307 Cov.: 30 AF XY: 0.0748 AC XY: 5554 AN XY: 74248

Gnomad4 AFR AF: 0.245

Gnomad4 AMR AF: 0.0310

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.0814

Gnomad4 SAS AF: 0.0323

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.0672

Alfa AF: 0.0372 Hom.: 122

Bravo AF: 0.0869

Asia WGS AF: 0.0740 AC: 257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2023

- -

Ehlers-Danlos syndrome, type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.12
Dann	Benign	0.54

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: rs28413125; hg19: chr2-189861962; COSMIC: COSV58584466; COSMIC: COSV58584466;