2-188999354-G-A

Variant names:

• chr2-188999354-G-A
• rs1800255
• NM_000090.4:c.2092G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000090.4(COL3A1):​c.2092G>A​(p.Ala698Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,598,508 control chromosomes in the GnomAD database, including 49,266 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A698S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.22 (3858 hom., cov: 32)
  • Exomes 𝑓: 0.25 (45408 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.112
• Publications: 101 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 -17 ACMG points.

• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000090.4
• PP2: Missense variant in the COL3A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 495 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 4.0879 (above the threshold of 3.09). Trascript score misZ: 4.5995 (above the threshold of 3.09). GenCC associations: The gene is linked to Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, autosomal dominant Ehlers-Danlos syndrome, vascular type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035955012).
• BP6: Variant 2-188999354-G-A is Benign according to our data. Variant chr2-188999354-G-A is described in ClinVar as Benign. ClinVar VariationId is 17205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.29 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.2092G>A	p.Ala698Thr	missense	Exon 30 of 51	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.2092G>A	p.Ala698Thr	missense	Exon 30 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.1993G>A	p.Ala665Thr	missense	Exon 29 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.2083G>A	p.Ala695Thr	missense	Exon 30 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32870 AN: 151956 Hom.: 3855 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.317

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.241

GnomAD2 exomes AF: 0.249 AC: 54823 AN: 220080 AF XY: 0.258

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.224

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.249 AC: 360083 AN: 1446434 Hom.: 45408 Cov.: 37 AF XY: 0.252 AC XY: 181090 AN XY: 718026

African (AFR) AF: 0.118 AC: 3919 AN: 33268

American (AMR) AF: 0.242 AC: 10128 AN: 41840

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 7726 AN: 25776

East Asian (EAS) AF: 0.249 AC: 9703 AN: 39000

South Asian (SAS) AF: 0.309 AC: 26035 AN: 84392

European-Finnish (FIN) AF: 0.257 AC: 13475 AN: 52484

Middle Eastern (MID) AF: 0.330 AC: 1897 AN: 5744

European-Non Finnish (NFE) AF: 0.247 AC: 272306 AN: 1104134

Other (OTH) AF: 0.249 AC: 14894 AN: 59796

GnomAD4 genome AF: 0.216 AC: 32876 AN: 152074 Hom.: 3858 Cov.: 32 AF XY: 0.218 AC XY: 16217 AN XY: 74342

African (AFR) AF: 0.121 AC: 5000 AN: 41482

American (AMR) AF: 0.232 AC: 3549 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1043 AN: 3470

East Asian (EAS) AF: 0.231 AC: 1196 AN: 5170

South Asian (SAS) AF: 0.303 AC: 1458 AN: 4814

European-Finnish (FIN) AF: 0.259 AC: 2750 AN: 10598

Middle Eastern (MID) AF: 0.328 AC: 95 AN: 290

European-Non Finnish (NFE) AF: 0.253 AC: 17157 AN: 67948

Other (OTH) AF: 0.241 AC: 510 AN: 2114

Alfa AF: 0.240 Hom.: 12090

Bravo AF: 0.210

TwinsUK AF: 0.242 AC: 899

ALSPAC AF: 0.244 AC: 940

ESP6500AA AF: 0.134 AC: 592

ESP6500EA AF: 0.255 AC: 2190

ExAC AF: 0.231 AC: 27868

Asia WGS AF: 0.235 AC: 817 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	Ehlers-Danlos syndrome, type 4 (5)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	2	not provided (2)
-	-	1	COLLAGEN TYPE III POLYMORPHISM (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (1)
-	-	1	Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.11
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.20
Sift	Benign	0.23	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.073
MPC		0.61
ClinPred		0.018	T
GERP RS		0.87
Varity_R		0.053
gMVP		0.14
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs1800255; hg19: chr2-189864080; COSMIC: COSV58587972; COSMIC: COSV58587972;