rs1555573484

chr17-50193041-GCT-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000088.4(COL1A1):c.1772_1773del(p.Glu591AlafsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.06

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-50193041-GCT-G is Pathogenic according to our data. Variant chr17-50193041-GCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 456739.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.1772_1773del	p.Glu591AlafsTer42	frameshift_variant	26/51	ENST00000225964.10
COL1A1	XM_005257058.5	c.1772_1773del	p.Glu591AlafsTer42	frameshift_variant	26/49
COL1A1	XM_011524341.2	c.1574_1575del	p.Glu525AlafsTer42	frameshift_variant	23/48
COL1A1	XM_005257059.5	c.958-350_958-349del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.1772_1773del	p.Glu591AlafsTer42	frameshift_variant	26/51	1	NM_000088.4	P1
COL1A1	ENST00000476387.1	n.121_122del		non_coding_transcript_exon_variant	2/9	2

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: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 17, 2020

While this particular variant has not been reported in the literature, loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 9443882, 9295084, 7942841). For these reasons, this variant has been classified as Pathogenic. This sequence change deletes 2 nucleotides from exon 26 of the COL1A1 mRNA (c.1772_1773delAG), causing a frameshift at codon 591. This creates a premature translational stop signal (p.Glu591Alafs*42) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555573484; hg19: chr17-48270402;