rs794727287

Positions:

• chr6-108064285-ACT-A

Variant summary

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

The NM_014028.4(OSTM1):​c.415_416del​(p.Gln140GlufsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OSTM1 NM_014028.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.30

Genes affected

OSTM1 (HGNC:21652): (osteoclastogenesis associated transmembrane protein 1) This gene encodes a protein that may be involved in the degradation of G proteins via the ubiquitin-dependent proteasome pathway. The encoded protein binds to members of subfamily A of the regulator of the G-protein signaling (RGS) family through an N-terminal leucine-rich region. This protein also has a central RING finger-like domain and E3 ubiquitin ligase activity. This protein is highly conserved from flies to humans. Defects in this gene may cause the autosomal recessive, infantile malignant form of osteopetrosis. [provided by RefSeq, Jul 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 6-108064285-ACT-A is Pathogenic according to our data. Variant chr6-108064285-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 195291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-108064285-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OSTM1	NM_014028.4	c.415_416del	p.Gln140GlufsTer11	frameshift_variant	2/6	ENST00000193322.8
OSTM1	XM_047418679.1	c.415_416del	p.Gln140GlufsTer11	frameshift_variant	2/7
OSTM1	XM_047418680.1	c.415_416del	p.Gln140GlufsTer11	frameshift_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OSTM1	ENST00000193322.8	c.415_416del	p.Gln140GlufsTer11	frameshift_variant	2/6	1	NM_014028.4	P1

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive osteopetrosis 5 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 16, 2021	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	May 08, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 13, 2023	This sequence change creates a premature translational stop signal (p.Gln140Glufs*11) in the OSTM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OSTM1 are known to be pathogenic (PMID: 12627228, 15108279, 16813530). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with malignant infantile osteopetrosis and/or skeletal dysplasia (PMID: 15108279, 29620724). 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)		0.0		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: rs794727287; hg19: chr6-108385489;