9-75133399-A-G

Variant names:

• chr9-75133399-A-G
• rs201675512
• NM_012383.5:c.356A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012383.5(OSTF1):​c.356A>G​(p.Lys119Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,577,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: OSTF1 NM_012383.5 missense, splice_region
• Scores: Splicing: ADA: 0.0002140
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84
• Publications: 0 publications found

Genes affected

OSTF1 (HGNC:8510): (osteoclast stimulating factor 1) Osteoclast-stimulating factor-1 is an intracellular protein produced by osteoclasts that indirectly induces osteoclast formation and bone resorption (Reddy et al., 1998 [PubMed 10092216]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07635835).
• BS2: High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012383.5. 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
	OSTF1	NM_012383.5	MANE Select	c.356A>G	p.Lys119Arg	missense splice_region	Exon 6 of 10	NP_036515.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSTF1	ENST00000346234.7	TSL:1 MANE Select	c.356A>G	p.Lys119Arg	missense splice_region	Exon 6 of 10	ENSP00000340836.6	Q92882
	OSTF1	ENST00000857346.1		c.404A>G	p.Lys135Arg	missense splice_region	Exon 8 of 12	ENSP00000527405.1
	OSTF1	ENST00000857342.1		c.365A>G	p.Lys122Arg	missense splice_region	Exon 6 of 10	ENSP00000527401.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000523 AC: 13 AN: 248462 AF XY: 0.0000447

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000597

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000886

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000547 AC: 78 AN: 1425090 Hom.: 0 Cov.: 23 AF XY: 0.0000548 AC XY: 39 AN XY: 711068

African (AFR) AF: 0.00 AC: 0 AN: 32668

American (AMR) AF: 0.0000454 AC: 2 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25882

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39442

South Asian (SAS) AF: 0.00 AC: 0 AN: 84900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5710

European-Non Finnish (NFE) AF: 0.0000611 AC: 66 AN: 1079930

Other (OTH) AF: 0.000102 AC: 6 AN: 59104

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74496

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000110

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.37	N
PhyloP100		2.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.10
Sift	Benign	0.53	T
Sift4G	Benign	0.60	T
Polyphen		0.0040	B
Vest4		0.23
MVP		0.56
MPC		0.16
ClinPred		0.28	T
GERP RS		-0.42
Varity_R		0.084
gMVP		0.37
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 2

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

Other links and lift over

dbSNP: rs201675512; hg19: chr9-77748315; COSMIC: COSV60548910;