NM_000090.4:c.2035G>A

Variant names:

• chr2-188999297-G-A
• rs41263773
• NM_000090.4:c.2035G>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.2035G>A​(p.Ala679Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00727 in 1,576,684 control chromosomes in the GnomAD database, including 59 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (56 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.415
• Publications: 14 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 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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=0.0066823065).
• BP6: Variant 2-188999297-G-A is Benign according to our data. Variant chr2-188999297-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35964.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 = 0.00575 (875/152238) while in subpopulation NFE AF = 0.0093 (633/68032). AF 95% confidence interval is 0.0087. There are 3 homozygotes in GnomAd4. There are 438 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.2035G>A	p.Ala679Thr	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.2035G>A	p.Ala679Thr	missense	Exon 30 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.1936G>A	p.Ala646Thr	missense	Exon 29 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.2026G>A	p.Ala676Thr	missense	Exon 30 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 875 AN: 152120 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00930

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00550 AC: 1037 AN: 188674 AF XY: 0.00559

Gnomad AFR exome AF: 0.000689

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.000559

Gnomad EAS exome AF: 0.00222

Gnomad FIN exome AF: 0.00717

Gnomad NFE exome AF: 0.00951

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00743 AC: 10590 AN: 1424446 Hom.: 56 Cov.: 32 AF XY: 0.00725 AC XY: 5115 AN XY: 705086

African (AFR) AF: 0.00123 AC: 40 AN: 32606

American (AMR) AF: 0.00253 AC: 98 AN: 38808

Ashkenazi Jewish (ASJ) AF: 0.000826 AC: 21 AN: 25420

East Asian (EAS) AF: 0.00111 AC: 42 AN: 37746

South Asian (SAS) AF: 0.00122 AC: 100 AN: 81792

European-Finnish (FIN) AF: 0.00831 AC: 426 AN: 51290

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5694

European-Non Finnish (NFE) AF: 0.00874 AC: 9546 AN: 1092090

Other (OTH) AF: 0.00522 AC: 308 AN: 59000

GnomAD4 genome AF: 0.00575 AC: 875 AN: 152238 Hom.: 3 Cov.: 33 AF XY: 0.00588 AC XY: 438 AN XY: 74428

African (AFR) AF: 0.00190 AC: 79 AN: 41518

American (AMR) AF: 0.00418 AC: 64 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4820

European-Finnish (FIN) AF: 0.00764 AC: 81 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00930 AC: 633 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00754 Hom.: 14

Bravo AF: 0.00470

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00531 AC: 640

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	2	Ehlers-Danlos syndrome, type 4 (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (1)
-	-	1	Familial aortopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0067	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.96	L
PhyloP100		0.41
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.25
Sift	Benign	0.42	T
Sift4G	Benign	0.22	T
Polyphen		0.16	B
Vest4		0.37
MVP		0.81
MPC		0.61
ClinPred		0.0074	T
GERP RS		4.0
Varity_R		0.048
gMVP		0.22
Mutation Taster		=98/2	polymorphism

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: rs41263773; hg19: chr2-189864023;