NM_014028.4:c.*2517_*2518delGT

Variant names:

• chr6-108042266-TAC-T
• rs886060960
• NM_014028.4:c.*2517_*2518delGT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014028.4(OSTM1):​c.*2517_*2518delGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 6)
  • Failed GnomAD Quality Control
• Consequence: OSTM1 NM_014028.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.259
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.*2517_*2518delGT		3_prime_UTR	Exon 6 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.*2517_*2518delGT		3_prime_UTR	Exon 6 of 6	ENSP00000193322.3	Q86WC4
	OSTM1	ENST00000492130.2	TSL:1	n.*2219-4_*2219-3delGT		splice_region intron	N/A	ENSP00000514453.1	Q86WC4
	OSTM1	ENST00000699577.1		c.*2517_*2518delGT		3_prime_UTR	Exon 7 of 7	ENSP00000514450.1	A0A8V8TPT7

Frequencies

GnomAD3 genomes AF: 0.000673 AC: 23 AN: 34184 Hom.: 0 Cov.: 6

Gnomad AFR AF: 0.000807

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00123

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00259

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000746

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00219

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000673 AC: 23 AN: 34180 Hom.: 0 Cov.: 6 AF XY: 0.000442 AC XY: 7 AN XY: 15830

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000805 AC: 6 AN: 7452

American (AMR) AF: 0.00122 AC: 3 AN: 2450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1094

East Asian (EAS) AF: 0.00260 AC: 4 AN: 1538

South Asian (SAS) AF: 0.00 AC: 0 AN: 1442

European-Finnish (FIN) AF: 0.000746 AC: 1 AN: 1340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 46

European-Non Finnish (NFE) AF: 0.000441 AC: 8 AN: 18146

Other (OTH) AF: 0.00217 AC: 1 AN: 460

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00641 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Osteopetrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886060960; hg19: chr6-108363470;