Genetic Variant OSTM1:c.*2488dupT (chr6-108042296-T-TA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_014028.4(OSTM1):c.*2488dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 140,120 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00039 ( 0 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

Not reported in ClinVar

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 -4 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000393 (55/140120) while in subpopulation NFE AF = 0.000621 (40/64434). AF 95% confidence interval is 0.000468. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.*2488dupT		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.*2488dupT	3_prime_UTR	Exon 6 of 6	ENSP00000193322.3	Q86WC4
OSTM1	ENST00000492130.2	TSL:1	n.*2219-33dupT	intron	N/A	ENSP00000514453.1	Q86WC4
OSTM1	ENST00000699577.1		c.*2488dupT	3_prime_UTR	Exon 7 of 7	ENSP00000514450.1	A0A8V8TPT7

Frequencies

GnomAD3 genomes

AF:

0.000393

AC:

AN:

140070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000210

Gnomad AMI

AF:

0.00115

Gnomad AMR

AF:

0.0000719

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000206

Gnomad SAS

AF:

0.000452

Gnomad FIN

AF:

0.000126

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000621

Gnomad OTH

AF:

0.000529

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:

0.000393

AC:

AN:

140120

Hom.:

Cov.:

AF XY:

0.000354

AC XY:

AN XY:

67752

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

38222

American (AMR)

AF:

0.0000718

AC:

AN:

13930

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3304

East Asian (EAS)

AF:

0.000206

AC:

AN:

4848

South Asian (SAS)

AF:

0.000453

AC:

AN:

4414

European-Finnish (FIN)

AF:

0.000126

AC:

AN:

7924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.000621

AC:

AN:

64434

Other (OTH)

AF:

0.000525

AC:

AN:

1906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000371

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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6-108042296-TAA-TAAA

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