chr2-188997322-G-C

Variant names:

• chr2-188997322-G-C
• rs7579815
• NM_000090.4:c.1816-14G>C

Variant summary

Our verdict is Benign. The variant received -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:13
• Conservation: PhyloP100: -0.685
• Publications: 6 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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 136847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

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.1816-14G>C		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.1816-14G>C		intron	N/A	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.1717-14G>C		intron	N/A	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.1807-14G>C		intron	N/A	ENSP00000549260.1

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

GnomAD2 exomes AF: 0.123 AC: 30889 AN: 251198 AF XY: 0.125

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 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

African (AFR) AF: 0.225 AC: 7499 AN: 33382

American (AMR) AF: 0.0824 AC: 3682 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3715 AN: 26120

East Asian (EAS) AF: 0.000982 AC: 39 AN: 39700

South Asian (SAS) AF: 0.108 AC: 9328 AN: 86180

European-Finnish (FIN) AF: 0.0984 AC: 5253 AN: 53404

Middle Eastern (MID) AF: 0.199 AC: 1146 AN: 5764

European-Non Finnish (NFE) AF: 0.149 AC: 164580 AN: 1108256

Other (OTH) AF: 0.142 AC: 8543 AN: 60278

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

African (AFR) AF: 0.217 AC: 8981 AN: 41344

American (AMR) AF: 0.132 AC: 2014 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 489 AN: 3470

East Asian (EAS) AF: 0.00427 AC: 22 AN: 5158

South Asian (SAS) AF: 0.106 AC: 507 AN: 4804

European-Finnish (FIN) AF: 0.0907 AC: 958 AN: 10566

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.149 AC: 10128 AN: 67968

Other (OTH) AF: 0.159 AC: 335 AN: 2108

Alfa AF: 0.146 Hom.: 297

Bravo AF: 0.161

Asia WGS AF: 0.0990 AC: 343 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Ehlers-Danlos syndrome, type 4 (4)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)
-	-	1	Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.63
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

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: rs7579815; hg19: chr2-189862048;