rs1114167391

Variant names:

• chr17-50190353-CG-C
• rs1114167391
• NM_000088.4:c.2424delC

Your query was ambiguous. Multiple possible variants found:

• chr17-50190353-CG-C
• chr17-50190353-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000088.4(COL1A1):​c.2424delC​(p.Gly809AlafsTer299) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL1A1 NM_000088.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.934

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50190353-CG-C is Pathogenic according to our data. Variant chr17-50190353-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 580032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50190353-CG-C is described in Lovd as [Pathogenic]. Variant chr17-50190353-CG-C is described in Lovd as [Pathogenic]. Variant chr17-50190353-CG-C is described in Lovd as [Pathogenic]. Variant chr17-50190353-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.2424delC	p.Gly809AlafsTer299	frameshift_variant	Exon 35 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.2226delC	p.Gly743AlafsTer299	frameshift_variant	Exon 32 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.2424delC	p.Gly809AlafsTer209	frameshift_variant	Exon 35 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.1506delC	p.Gly503AlafsTer299	frameshift_variant	Exon 22 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.2424delC	p.Gly809AlafsTer299	frameshift_variant	Exon 35 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000494334.1	n.351delC		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459694 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726298

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:2

Sep 10, 2024

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This deletion causes a shift in the reading frame resulting in a premature stop codon. Loss of function variants in the gene COL1A1 are a known mechanism of disease. In gnomAD exomes, this variant has been reported 4 times (v4.1.0). This variant has been previously reported as pathogenic in ClinVar (VCV000580032.9). This variant has been reported in literature in patients presenting with osteogenesis imperfecta (PMID: 21667357). According to the available evidence, this variant is considered to be pathogenic. -

Apr 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly809Alafs*299) in the COL1A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with osteogenesis imperfecta, type I (PMID: 21667357). ClinVar contains an entry for this variant (Variation ID: 580032). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1114167391; hg19: chr17-48267714;