rs1801183

Variant names:

• chr2-188998698-C-A
• rs1801183
• NM_000090.4:c.2002C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-188998698-C-A
• chr2-188998698-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000090.4(COL3A1):​c.2002C>A​(p.Pro668Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,613,868 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P668S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (13 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: 2.77
• Publications: 16 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 -10 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 autosomal dominant Ehlers-Danlos syndrome, vascular type, Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.020303607).
• BP6: Variant 2-188998698-C-A is Benign according to our data. Variant chr2-188998698-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 199726.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00112 (171/152244) while in subpopulation SAS AF = 0.00998 (48/4812). AF 95% confidence interval is 0.00773. There are 1 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.2002C>A	p.Pro668Thr	missense	Exon 29 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.2002C>A	p.Pro668Thr	missense	Exon 29 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.1903C>A	p.Pro635Thr	missense	Exon 28 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.1993C>A	p.Pro665Thr	missense	Exon 29 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152126 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00997

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00173 AC: 435 AN: 251170 AF XY: 0.00200

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00154 AC: 2245 AN: 1461624 Hom.: 13 Cov.: 32 AF XY: 0.00169 AC XY: 1229 AN XY: 727108

African (AFR) AF: 0.000299 AC: 10 AN: 33474

American (AMR) AF: 0.000738 AC: 33 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00383 AC: 100 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00817 AC: 705 AN: 86244

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53404

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5764

European-Non Finnish (NFE) AF: 0.00113 AC: 1254 AN: 1111856

Other (OTH) AF: 0.00162 AC: 98 AN: 60376

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152244 Hom.: 1 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74414

African (AFR) AF: 0.000169 AC: 7 AN: 41542

American (AMR) AF: 0.00163 AC: 25 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

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

South Asian (SAS) AF: 0.00998 AC: 48 AN: 4812

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00151 Hom.: 6

Bravo AF: 0.000971

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00174 AC: 211

EpiCase AF: 0.00125

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	1	2	Ehlers-Danlos syndrome, type 4 (3)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	1	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	0.064
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.020	T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.6	L
PhyloP100		2.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.61
Sift	Benign	0.031	D
Sift4G	Uncertain	0.033	D
Polyphen		0.99	D
Vest4		0.61
MVP		0.84
MPC		0.70
ClinPred		0.039	T
GERP RS		5.9
Varity_R		0.21
gMVP		0.55
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.030		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: rs1801183; hg19: chr2-189863424; COSMIC: COSV99049391; COSMIC: COSV99049391;