rs72667016

Positions:

• 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 ENST00000225964.10(COL1A1):​c.432del​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. P144P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: COL1A1 ENST00000225964.10 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/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.432del	p.Gly145AspfsTer120	frameshift_variant	5/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.432del	p.Gly145AspfsTer120	frameshift_variant	5/48		XP_011522643.1
COL1A1	XM_005257058.5	c.432del	p.Gly145AspfsTer120	frameshift_variant	5/49		XP_005257115.2
COL1A1	XM_005257059.5	c.432del	p.Gly145AspfsTer120	frameshift_variant	5/38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.432del	p.Gly145AspfsTer120	frameshift_variant	5/51	1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000507689.1			downstream_gene_variant		2		ENSP00000460459
COL1A1	ENST00000474644.1			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

Pathogenic, no assertion criteria provided

clinical testing

Autoinflammatory diseases unit, CHU de Montpellier

Oct 01, 2024

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 30, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1357973). This variant is also known as p.P144fsX120. This premature translational stop signal has been observed in individual(s) with osteogenesis imperfecta (PMID: 16786509). 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 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). -

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;