chr2-189008117-G-T

Variant names:

• chr2-189008117-G-T
• rs587779578
• NM_000090.4:c.3500G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000090.4(COL3A1):​c.3500G>T​(p.Gly1167Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1167D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0
• Publications: 0 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ENSG00000295704 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000090.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 2-189008117-G-T is Pathogenic according to our data. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.3500G>T	p.Gly1167Val	missense_variant	Exon 47 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.3500G>T	p.Gly1167Val	missense_variant	Exon 47 of 51	1	NM_000090.4	ENSP00000304408.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:1

-

Collagen Diagnostic Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.6	H;.
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Pathogenic	1.0
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.99		Loss of relative solvent accessibility (P = 0.0071);.;
MVP		0.97
MPC		0.26
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs587779578; hg19: chr2-189872843; COSMIC: COSV100482640; COSMIC: COSV100482640;