rs794727287

Variant names:

• chr6-108064285-ACT-A
• rs794727287
• NM_014028.4:c.415_416delAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014028.4(OSTM1):​c.415_416delAG​(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
• Publications: 1 publications found

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]

OSTM1 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• infantile osteopetrosis with neuroaxonal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 195291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014028.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSTM1	NM_014028.4	MANE Select	c.415_416delAG	p.Gln140GlufsTer11	frameshift	Exon 2 of 6	NP_054747.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSTM1	ENST00000193322.8	TSL:1 MANE Select	c.415_416delAG	p.Gln140GlufsTer11	frameshift	Exon 2 of 6	ENSP00000193322.3	Q86WC4
	OSTM1	ENST00000492130.2	TSL:1	n.415_416delAG		non_coding_transcript_exon	Exon 2 of 7	ENSP00000514453.1	Q86WC4
	OSTM1	ENST00000699577.1		c.415_416delAG	p.Gln140GlufsTer11	frameshift	Exon 2 of 7	ENSP00000514450.1	A0A8V8TPT7

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal recessive osteopetrosis 5 (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794727287; hg19: chr6-108385489;