Genetic Variant OSTM1:c.*2488delT (chr6-108042296-TA-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_014028.4(OSTM1):c.*2488delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 140,126 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0060 ( 9 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OSTM1
NM_014028.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.05

Publications

0 publications found

Variant links:

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

OSTM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00601 (842/140126) while in subpopulation AFR AF = 0.0204 (778/38228). AF 95% confidence interval is 0.0192. There are 9 homozygotes in GnomAd4. There are 377 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 9 AR gene

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.*2488delT		3_prime_UTR	Exon 6 of 6	NP_054747.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OSTM1	ENST00000193322.8	TSL:1 MANE Select	c.*2488delT	3_prime_UTR	Exon 6 of 6	ENSP00000193322.3	Q86WC4
OSTM1	ENST00000492130.2	TSL:1	n.*2219-33delT	intron	N/A	ENSP00000514453.1	Q86WC4
OSTM1	ENST00000699577.1		c.*2488delT	3_prime_UTR	Exon 7 of 7	ENSP00000514450.1	A0A8V8TPT7

Frequencies

GnomAD3 genomes

AF:

0.00601

AC:

842

AN:

140076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0204

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000791

Gnomad ASJ

AF:

0.000605

Gnomad EAS

AF:

0.000206

Gnomad SAS

AF:

0.00475

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00345

Gnomad NFE

AF:

0.000295

Gnomad OTH

AF:

0.00477

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.00601

AC:

842

AN:

140126

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

377

AN XY:

67752

show subpopulations

African (AFR)

AF:

0.0204

AC:

778

AN:

38228

American (AMR)

AF:

0.000790

AC:

AN:

13930

Ashkenazi Jewish (ASJ)

AF:

0.000605

AC:

AN:

3304

East Asian (EAS)

AF:

0.000206

AC:

AN:

4850

South Asian (SAS)

AF:

0.00476

AC:

AN:

4414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7920

Middle Eastern (MID)

AF:

0.00373

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.000295

AC:

AN:

64440

Other (OTH)

AF:

0.00473

AC:

AN:

1902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Osteopetrosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over