Genetic Variant SPP1:p.Asp94Asp (chr4-87981540-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_001040058.2(SPP1):c.282T>C(p.Asp94Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,613,978 control chromosomes in the GnomAD database, including 68,759 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.27 ( 6164 hom., cov: 32)

Exomes 𝑓: 0.28 ( 62595 hom. )

Consequence

SPP1
NM_001040058.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.69

Variant links:

Genes affected

SPP1 (HGNC:11255): (secreted phosphoprotein 1) The protein encoded by this gene is involved in the attachment of osteoclasts to the mineralized bone matrix. The encoded protein is secreted and binds hydroxyapatite with high affinity. The osteoclast vitronectin receptor is found in the cell membrane and may be involved in the binding to this protein. This protein is also a cytokine that upregulates expression of interferon-gamma and interleukin-12. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

SPP1 links:

ENSG00000286618 (HGNC:):

ENSG00000286618 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP7

Synonymous conserved (PhyloP=-2.69 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPP1	NM_001040058.2 link	c.282T>C	p.Asp94Asp	synonymous_variant	Exon 6 of 7	ENST00000395080.8	NP_001035147.1	P10451-1A0A024RDE2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPP1	ENST00000395080.8 link	c.282T>C	p.Asp94Asp	synonymous_variant	Exon 6 of 7	1	NM_001040058.2	ENSP00000378517.3		P10451-1

Frequencies

GnomAD3 genomes

AF:

0.269

AC:

40870

AN:

152028

Hom.:

6165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.191

Gnomad AMR

AF:

0.328

Gnomad ASJ

AF:

0.314

Gnomad EAS

AF:

0.691

Gnomad SAS

AF:

0.342

Gnomad FIN

AF:

0.289

Gnomad MID

AF:

0.415

Gnomad NFE

AF:

0.268

Gnomad OTH

AF:

0.330

GnomAD3 exomes

AF:

0.324

AC:

81499

AN:

251362

Hom.:

15100

AF XY:

0.322

AC XY:

43758

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.383

Gnomad ASJ exome

AF:

0.321

Gnomad EAS exome

AF:

0.706

Gnomad SAS exome

AF:

0.336

Gnomad FIN exome

AF:

0.288

Gnomad NFE exome

AF:

0.270

Gnomad OTH exome

AF:

0.321

GnomAD4 exome

AF:

0.281

AC:

411090

AN:

1461832

Hom.:

62595

Cov.:

AF XY:

0.283

AC XY:

206036

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.175

Gnomad4 AMR exome

AF:

0.378

Gnomad4 ASJ exome

AF:

0.313

Gnomad4 EAS exome

AF:

0.678

Gnomad4 SAS exome

AF:

0.333

Gnomad4 FIN exome

AF:

0.289

Gnomad4 NFE exome

AF:

0.260

Gnomad4 OTH exome

AF:

0.302

GnomAD4 genome

AF:

0.269

AC:

40899

AN:

152146

Hom.:

6164

Cov.:

AF XY:

0.271

AC XY:

20184

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.176

Gnomad4 AMR

AF:

0.328

Gnomad4 ASJ

AF:

0.314

Gnomad4 EAS

AF:

0.690

Gnomad4 SAS

AF:

0.341

Gnomad4 FIN

AF:

0.289

Gnomad4 NFE

AF:

0.268

Gnomad4 OTH

AF:

0.334

Alfa

AF:

0.280

Hom.:

14071

Bravo

AF:

0.274

Asia WGS

AF:

0.499

AC:

1736

AN:

3478

EpiCase

AF:

0.286

EpiControl

AF:

0.289

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.23

DANN

Benign

0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over