rs1555574417

Positions:

• chr17-50196543-ATA-AATTCTGATCTAC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000088.4(COL1A1):​c.859-17_859-16delinsGTAGATCAGAAT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.17

Genes affected

COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50196544-TA-ATTCTGATCTAC is Pathogenic according to our data. Variant chr17-50196544-TA-ATTCTGATCTAC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447147.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.859-17_859-16delinsGTAGATCAGAAT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.859-17_859-16delinsGTAGATCAGAAT		splice_polypyrimidine_tract_variant, intron_variant			XP_005257115.2
COL1A1	XM_005257059.5	c.859-17_859-16delinsGTAGATCAGAAT		splice_polypyrimidine_tract_variant, intron_variant			XP_005257116.2
COL1A1	XM_011524341.2	c.859-17_859-16delinsGTAGATCAGAAT		splice_polypyrimidine_tract_variant, intron_variant			XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.859-17_859-16delinsGTAGATCAGAAT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000485870.1	n.51_52delinsGTAGATCAGAAT		non_coding_transcript_exon_variant	1/2	3
COL1A1	ENST00000495677.1	n.586-17_586-16delinsGTAGATCAGAAT		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2024

The c.859-17_859-16delTAinsGTAGATCAGAAT intronic variant begins 17 nucleotides before coding exon 13 of the COL1A1 gene. This variant results from a deletion of 2 and insertion of 12 nucleotides at nucleotide positions c.859-17 to c.859-16. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as likely pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 08, 2017

- -

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: rs1555574417; hg19: chr17-48273905;