rs72667016

Variant names:

• chr17-50199264-CG-C
• rs72667016
• NM_000088.4:c.432delC

Your query was ambiguous. Multiple possible variants found:

• chr17-50199264-CG-C
• chr17-50199264-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_000088.4(COL1A1):​c.432delC​(p.Gly145AspfsTer120) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000742 in 1,348,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: COL1A1 NM_000088.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.710

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-50199264-CG-C is Pathogenic according to our data. Variant chr17-50199264-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1357973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50199264-CG-C is described in Lovd as [Pathogenic]. Variant chr17-50199264-CG-C is described in Lovd as [Pathogenic]. Variant chr17-50199264-CG-C is described in Lovd as [Pathogenic]. Variant chr17-50199264-CG-C is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.432delC	p.Gly145AspfsTer120	frameshift_variant	Exon 5 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.432delC	p.Gly145AspfsTer120	frameshift_variant	Exon 5 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.432delC	p.Gly145AspfsTer120	frameshift_variant	Exon 5 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.432delC	p.Gly145AspfsTer120	frameshift_variant	Exon 5 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.432delC	p.Gly145AspfsTer120	frameshift_variant	Exon 5 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000507689.1	c.*24delC		downstream_gene_variant		2		ENSP00000460459.1
COL1A1	ENST00000474644.1	n.*13delC		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000742 AC: 10 AN: 1348446 Hom.: 0 Cov.: 31 AF XY: 0.00000455 AC XY: 3 AN XY: 659150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000452

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000276

Gnomad4 FIN exome AF: 0.0000436

Gnomad4 NFE exome AF: 0.00000381

Gnomad4 OTH exome AF: 0.0000180

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1

Oct 01, 2024

Autoinflammatory diseases unit, CHU de Montpellier

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 30, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33939306, 16786509) -

Osteogenesis imperfecta type I Pathogenic:1

Jun 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 1357973). For these reasons, this variant has been classified as Pathogenic. This variant is also known as p.P144fsX120. This sequence change creates a premature translational stop signal (p.Gly145Aspfs*120) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with osteogenesis imperfecta (PMID: 16786509). -

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: rs72667016; hg19: chr17-48276625;