rs138061246

Variant names:

• chr2-189008160-CG-C
• rs138061246
• NM_000090.4:c.3525+19delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000090.4(COL3A1):​c.3525+19delG 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
• Publications: 2 publications found

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]

COL3A1 Gene-Disease associations (from GenCC):

• autosomal dominant Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000295704 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000090.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	NM_000090.4	MANE Select	c.3525+19delG		intron	N/A	NP_000081.2	P02461-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	ENST00000304636.9	TSL:1 MANE Select	c.3525+19delG		intron	N/A	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.3426+19delG		intron	N/A	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.3516+19delG		intron	N/A	ENSP00000549260.1

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

GnomAD2 exomes AF: 0.00994 AC: 2275 AN: 228966 AF XY: 0.0103

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 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

African (AFR) AF: 0.00273 AC: 90 AN: 32914

American (AMR) AF: 0.00622 AC: 267 AN: 42946

Ashkenazi Jewish (ASJ) AF: 0.00609 AC: 157 AN: 25760

East Asian (EAS) AF: 0.0000764 AC: 3 AN: 39286

South Asian (SAS) AF: 0.00735 AC: 618 AN: 84138

European-Finnish (FIN) AF: 0.00589 AC: 311 AN: 52768

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5696

European-Non Finnish (NFE) AF: 0.0187 AC: 20353 AN: 1086854

Other (OTH) AF: 0.0132 AC: 781 AN: 59290

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

African (AFR) AF: 0.00310 AC: 129 AN: 41560

American (AMR) AF: 0.00752 AC: 115 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00706 AC: 34 AN: 4816

European-Finnish (FIN) AF: 0.00462 AC: 49 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1172 AN: 68018

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00783 Hom.: 5

Bravo AF: 0.0113

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Ehlers-Danlos syndrome, type 4 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs138061246; hg19: chr2-189872886;