NM_000090.4:c.2056C>G

Variant names:

• chr2-188999318-C-G
• rs41263775
• NM_000090.4:c.2056C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1

The NM_000090.4(COL3A1):​c.2056C>G​(p.Pro686Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,589,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. P686H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.627
• Publications: 5 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 -13 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 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=0.013361037).
• BP6: Variant 2-188999318-C-G is Benign according to our data. Variant chr2-188999318-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 199698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00133 (203/152276) while in subpopulation AFR AF = 0.00479 (199/41546). AF 95% confidence interval is 0.00424. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2056C>G	p.Pro686Ala	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.2056C>G	p.Pro686Ala	missense	Exon 30 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.1957C>G	p.Pro653Ala	missense	Exon 29 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.2047C>G	p.Pro683Ala	missense	Exon 30 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00480

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000344 AC: 71 AN: 206110 AF XY: 0.000298

Gnomad AFR exome AF: 0.00502

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 187 AN: 1437074 Hom.: 0 Cov.: 32 AF XY: 0.000112 AC XY: 80 AN XY: 712496

African (AFR) AF: 0.00494 AC: 163 AN: 32998

American (AMR) AF: 0.000296 AC: 12 AN: 40550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25578

East Asian (EAS) AF: 0.00 AC: 0 AN: 38504

South Asian (SAS) AF: 0.00 AC: 0 AN: 83156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52066

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099006

Other (OTH) AF: 0.000185 AC: 11 AN: 59492

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74464

African (AFR) AF: 0.00479 AC: 199 AN: 41546

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.00147

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000355 AC: 43

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.63
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.24
Sift	Benign	0.46	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.26
MVP		0.60
MPC		0.61
ClinPred		0.010	T
GERP RS		1.9
Varity_R		0.056
gMVP		0.25
Mutation Taster		=84/16	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: rs41263775; hg19: chr2-189864044;