rs2271683

Variant names:

• chr2-189009011-A-G
• rs2271683
• NM_000090.4:c.3613A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000090.4(COL3A1):​c.3613A>G​(p.Ile1205Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,168 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I1205I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (111 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.91
• Publications: 18 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 -19 ACMG points.

• 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=0.0019847155).
• BP6: Variant 2-189009011-A-G is Benign according to our data. Variant chr2-189009011-A-G is described in ClinVar as Benign. ClinVar VariationId is 136856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.054 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.3613A>G	p.Ile1205Val	missense	Exon 48 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.3613A>G	p.Ile1205Val	missense	Exon 48 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.3514A>G	p.Ile1172Val	missense	Exon 47 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.3604A>G	p.Ile1202Val	missense	Exon 48 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 362 AN: 152160 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0595

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00443 AC: 1114 AN: 251388 AF XY: 0.00398

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0529

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00247 AC: 3612 AN: 1461892 Hom.: 111 Cov.: 30 AF XY: 0.00238 AC XY: 1734 AN XY: 727246

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0755 AC: 2996 AN: 39700

South Asian (SAS) AF: 0.00166 AC: 143 AN: 86258

European-Finnish (FIN) AF: 0.00273 AC: 146 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1112012

Other (OTH) AF: 0.00298 AC: 180 AN: 60396

GnomAD4 genome AF: 0.00237 AC: 361 AN: 152276 Hom.: 6 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74458

African (AFR) AF: 0.000144 AC: 6 AN: 41564

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0595 AC: 308 AN: 5178

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4824

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68006

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

Alfa AF: 0.00158 Hom.: 13

Bravo AF: 0.00247

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00447 AC: 543

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ehlers-Danlos syndrome, type 4 (3)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.039
DANN	Benign	0.22
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.22
Sift	Benign	0.54	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.34
MPC		0.17
ClinPred		0.0018	T
GERP RS		-11
Varity_R		0.025
gMVP		0.42
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2271683; hg19: chr2-189873737; COSMIC: COSV58584374;