rs138061246

chr2-189008160-CG-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000090.4(COL3A1):c.3525+19del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,581,914 control chromosomes in the GnomAD database, including 239 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 31)
  • Exomes 𝑓: 0.016 (214 hom.)
• Consequence: COL3A1 NM_000090.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.389

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 -16 ACMG points.

• BP6: Variant 2-189008160-CG-C is Benign according to our data. Variant chr2-189008160-CG-C is described in ClinVar as [Likely_benign]. Clinvar id is 199705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1684/152262) while in subpopulation NFE AF= 0.0172 (1172/68018). AF 95% confidence interval is 0.0164. There are 25 homozygotes in gnomad4. There are 750 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.3525+19del		intron_variant		ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.3525+19del		intron_variant		1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.3426+19del		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1685 AN: 152144 Hom.: 25 Cov.: 31

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00994 AC: 2275 AN: 228966 Hom.: 20 AF XY: 0.0103 AC XY: 1270 AN XY: 123204

Gnomad AFR exome AF: 0.00291

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.00500

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00705

Gnomad FIN exome AF: 0.00516

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0158 AC: 22589 AN: 1429652 Hom.: 214 Cov.: 25 AF XY: 0.0155 AC XY: 11045 AN XY: 711450

Gnomad4 AFR exome AF: 0.00273

Gnomad4 AMR exome AF: 0.00622

Gnomad4 ASJ exome AF: 0.00609

Gnomad4 EAS exome AF: 0.0000764

Gnomad4 SAS exome AF: 0.00735

Gnomad4 FIN exome AF: 0.00589

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0111 AC: 1684 AN: 152262 Hom.: 25 Cov.: 31 AF XY: 0.0101 AC XY: 750 AN XY: 74466

Gnomad4 AFR AF: 0.00310

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00706

Gnomad4 FIN AF: 0.00462

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00783 Hom.: 5

Bravo AF: 0.0113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: COL3A1 c.3525+19delG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0099 in 228966 control chromosomes, predominantly at a frequency of 0.016 within the Non-Finnish European subpopulation in the gnomAD database, including 14 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12800-folds over the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.3525+19delG in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2013	The variant is found in TAAD panel(s). -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 22, 2019	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 22, 2023

- -

Ehlers-Danlos syndrome, type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs138061246; hg19: chr2-189872886;