rs112185887

Variant names:

• chr2-188991017-G-A
• rs112185887
• NM_000090.4:c.812G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000090.4(COL3A1):​c.812G>A​(p.Arg271Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00272 in 1,613,090 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (13 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22 O:1
• Conservation: PhyloP100: 3.97
• Publications: 15 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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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=0.03814417).
• BP6: Variant 2-188991017-G-A is Benign according to our data. Variant chr2-188991017-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 161215.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 = 0.00169 (257/152212) while in subpopulation NFE AF = 0.00312 (212/67968). AF 95% confidence interval is 0.00278. 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.812G>A	p.Arg271Gln	missense	Exon 11 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.812G>A	p.Arg271Gln	missense	Exon 11 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.812G>A	p.Arg271Gln	missense	Exon 11 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.803G>A	p.Arg268Gln	missense	Exon 11 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152094 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00138 AC: 346 AN: 251132 AF XY: 0.00142

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00282 AC: 4123 AN: 1460878 Hom.: 13 Cov.: 31 AF XY: 0.00271 AC XY: 1973 AN XY: 726772

African (AFR) AF: 0.000538 AC: 18 AN: 33450

American (AMR) AF: 0.000738 AC: 33 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86164

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00344 AC: 3828 AN: 1111406

Other (OTH) AF: 0.00331 AC: 200 AN: 60338

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152212 Hom.: 1 Cov.: 32 AF XY: 0.00140 AC XY: 104 AN XY: 74412

African (AFR) AF: 0.000770 AC: 32 AN: 41568

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 67968

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00235 Hom.: 4

Bravo AF: 0.00182

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00136 AC: 165

EpiCase AF: 0.00377

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	5	Ehlers-Danlos syndrome, type 4 (6)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	3	not specified (3)
-	-	1	Connective tissue disorder (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	-0.18	N
PhyloP100		4.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.47
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.96	D
Vest4		0.59
MVP		0.95
MPC		0.72
ClinPred		0.019	T
GERP RS		6.0
Varity_R		0.069
gMVP		0.61
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs112185887; hg19: chr2-189855743; COSMIC: COSV58582303; COSMIC: COSV58582303;