rs397509372

Variant names:

• chr2-188996501-G-A
• rs397509372
• NM_000090.4:c.1761+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-188996501-G-A
• chr2-188996501-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000090.4(COL3A1):​c.1761+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: COL3A1 NM_000090.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.96
• Publications: 1 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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-188996501-G-A is Pathogenic according to our data. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-188996501-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 101209.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.1761+5G>A		splice_region_variant, intron_variant	Intron 24 of 50	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1761+5G>A		splice_region_variant, intron_variant	Intron 24 of 50	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.1662+5G>A		splice_region_variant, intron_variant	Intron 23 of 49	1		ENSP00000415346.2
COL3A1	ENST00000713745.1	c.1609-664G>A		intron_variant	Intron 22 of 48			ENSP00000519049.1
COL3A1	ENST00000713744.1	c.1761+5G>A		splice_region_variant, intron_variant	Intron 24 of 48			ENSP00000519048.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Dec 12, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1761+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 24 in the COL3A1 gene. This alteration has been reported in an individual with biochemically confirmed vascular Ehler-Danlos syndrome (vEDS, also known as type IV), and RNA analysis revealed exon skipping (Pepin MG et al. Genet. Med. 2014;16:881-8; personal communication from Collagen Diagnostic Laboratory). A likely pathogenic, functionally-validated splicing alteration at this nucleotide position (c.1761+5G>T) has also been associated with vEDS (Lee B et al. J. Biol. Chem. 1991;266:5256-9). This nucleotide position is highly conserved in available vertebrate species. This alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	33
DANN	Benign	0.94
PhyloP100		10
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.61		Position offset: -49
DS_DL_spliceai		0.53		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397509372; hg19: chr2-189861227;