6-108042414-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014028.4(OSTM1):c.*2371G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 25)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OSTM1 NM_014028.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.61

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OSTM1	NM_014028.4	c.*2371G>A		3_prime_UTR_variant	6/6	ENST00000193322.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OSTM1	ENST00000193322.8	c.*2371G>A		3_prime_UTR_variant	6/6	1	NM_014028.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 130 AN: 129206 Hom.: 1 Cov.: 25 FAILED QC

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000484

Gnomad ASJ AF: 0.000318

Gnomad EAS AF: 0.00221

Gnomad SAS AF: 0.00102

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00763

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.00230

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00105 AC: 136 AN: 129240 Hom.: 1 Cov.: 25 AF XY: 0.00110 AC XY: 68 AN XY: 61778

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.000645

Gnomad4 ASJ AF: 0.000318

Gnomad4 EAS AF: 0.00221

Gnomad4 SAS AF: 0.00102

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.00400

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive osteopetrosis 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.60
Dann	Benign	0.19

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: rs865891537; hg19: chr6-108363618;