rs587779425

chr2-188991716-GGCTGCAGTGAGTATA-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000090.4(COL3A1):c.951_951+14del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A316A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.26

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.006021359 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of -35, new splice context is: ctgGTgagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-188991716-GGCTGCAGTGAGTATA-G is Pathogenic according to our data. Variant chr2-188991716-GGCTGCAGTGAGTATA-G is described in ClinVar as [Pathogenic]. Clinvar id is 101111.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.951_951+14del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	13/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.951_951+14del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	13/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.951_951+14del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	13/50	1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Collagen Diagnostic Laboratory, University of Washington

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587779425; hg19: chr2-189856442;