rs35795890

Variant names:

• chr2-188997207-C-A
• rs35795890
• NM_000090.4:c.1804C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-188997207-C-A
• chr2-188997207-C-G
• chr2-188997207-C-T

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.1804C>A​(p.Pro602Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,613,986 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P602A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (5 hom., cov: 30)
  • Exomes 𝑓: 0.0056 (30 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 2.99
• 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)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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=0.019590318).
• BP6: Variant 2-188997207-C-A is Benign according to our data. Variant chr2-188997207-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00513 (781/152128) while in subpopulation AMR AF = 0.00883 (135/15282). AF 95% confidence interval is 0.00762. There are 5 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1804C>A	p.Pro602Thr	missense	Exon 25 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.1804C>A	p.Pro602Thr	missense	Exon 25 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.1705C>A	p.Pro569Thr	missense	Exon 24 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.1795C>A	p.Pro599Thr	missense	Exon 25 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 781 AN: 152010 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00885

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00293

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00620

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00455 AC: 1144 AN: 251446 AF XY: 0.00482

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00240

Gnomad NFE exome AF: 0.00662

Gnomad OTH exome AF: 0.00863

GnomAD4 exome AF: 0.00561 AC: 8200 AN: 1461858 Hom.: 30 Cov.: 33 AF XY: 0.00558 AC XY: 4056 AN XY: 727230

African (AFR) AF: 0.00376 AC: 126 AN: 33480

American (AMR) AF: 0.00440 AC: 197 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00539 AC: 141 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00148 AC: 128 AN: 86258

European-Finnish (FIN) AF: 0.00256 AC: 137 AN: 53416

Middle Eastern (MID) AF: 0.0231 AC: 133 AN: 5766

European-Non Finnish (NFE) AF: 0.00624 AC: 6935 AN: 1111986

Other (OTH) AF: 0.00667 AC: 403 AN: 60394

GnomAD4 genome AF: 0.00513 AC: 781 AN: 152128 Hom.: 5 Cov.: 30 AF XY: 0.00481 AC XY: 358 AN XY: 74370

African (AFR) AF: 0.00323 AC: 134 AN: 41482

American (AMR) AF: 0.00883 AC: 135 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00293 AC: 31 AN: 10592

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00621 AC: 422 AN: 68004

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00616 Hom.: 13

Bravo AF: 0.00558

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00440 AC: 534

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00782

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	Ehlers-Danlos syndrome, type 4 (4)
-	-	4	not specified (4)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	1	Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.43
Sift	Benign	0.26	T
Sift4G	Benign	0.19	T
Polyphen		0.50	P
Vest4		0.54
MVP		0.67
MPC		0.70
ClinPred		0.032	T
GERP RS		6.0
Varity_R		0.14
gMVP		0.51
Mutation Taster		=67/33	polymorphism

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: rs35795890; hg19: chr2-189861933;