rs1555571529

chr17-50185569-G-GCCACATC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000088.4(COL1A1):c.4327_4328insGATGTGG(p.Ala1443GlyfsTer110) variant causes a frameshift 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 (★). Synonymous variant affecting the same amino acid position (i.e. A1443A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: COL1A1 NM_000088.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50185569-G-GCCACATC is Pathogenic according to our data. Variant chr17-50185569-G-GCCACATC is described in ClinVar as [Pathogenic]. Clinvar id is 456790.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.4327_4328insGATGTGG	p.Ala1443GlyfsTer110	frameshift_variant	51/51	ENST00000225964.10
COL1A1	XM_005257058.5	c.4057_4058insGATGTGG	p.Ala1353GlyfsTer110	frameshift_variant	49/49
COL1A1	XM_005257059.5	c.3409_3410insGATGTGG	p.Ala1137GlyfsTer110	frameshift_variant	38/38
COL1A1	XM_011524341.2	c.4129_4130insGATGTGG	p.Ala1377GlyfsTer110	frameshift_variant	48/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.4327_4328insGATGTGG	p.Ala1443GlyfsTer110	frameshift_variant	51/51	1	NM_000088.4	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 14, 2017

For these reasons, this variant has been classified as Pathogenic. Two frameshift variants downstream of this variant (c.4329_4332dup and c.4357_4361del) have been determined to be pathogenic (PMID: 2295701, Invitae). All three variants results in a similar shift in the reading frame. This suggests the disruption of this region and extension of the COL1A1 protein are causative of disease. This variant is not present in population databases (ExAC no frequency). This sequence change inserts 7 nucleotides in exon 51 of the COL1A1 mRNA (c.4321_4327dupGATGTGG), causing a frameshift in the last exon at codon 1443. While this is not expected to result in nonsense mediated decay of the mRNA, it is predicted to alter the last 22 amino acids of the protein and extend it by an additional 88 amino acids (p.Ala1443Glyfs*110). This variant has not been reported in the literature in individuals with COL1A1-related disease. -

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: rs1555571529; hg19: chr17-48262930;