6-108042030-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014028.4(OSTM1):c.*2755A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0682 in 152,212 control chromosomes in the GnomAD database, including 693 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (693 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: OSTM1 NM_014028.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.758

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-108042030-T-C is Benign according to our data. Variant chr6-108042030-T-C is described in ClinVar as [Benign]. Clinvar id is 354933.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OSTM1	NM_014028.4	c.*2755A>G		3_prime_UTR_variant	6/6	ENST00000193322.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OSTM1	ENST00000193322.8	c.*2755A>G		3_prime_UTR_variant	6/6	1	NM_014028.4	P1

Frequencies

GnomAD3 genomes AF: 0.0680 AC: 10345 AN: 152094 Hom.: 685 Cov.: 31

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0413

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.0515

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0531

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0682 AC: 10383 AN: 152212 Hom.: 693 Cov.: 31 AF XY: 0.0673 AC XY: 5010 AN XY: 74440

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.0412

Gnomad4 ASJ AF: 0.0375

Gnomad4 EAS AF: 0.0513

Gnomad4 SAS AF: 0.00579

Gnomad4 FIN AF: 0.0299

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0402 Hom.: 120

Bravo AF: 0.0742

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive osteopetrosis 5 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.63
Dann	Benign	0.52

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: rs6921341; hg19: chr6-108363234;