4-87981540-T-C

Variant names:

• chr4-87981540-T-C
• rs4754
• NM_001040058.2:c.282T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69
• Publications: 75 publications found

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 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286618 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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	c.282T>C	p.Asp94Asp	synonymous_variant	Exon 6 of 7	ENST00000395080.8	NP_001035147.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40870 AN: 152028 Hom.: 6165 Cov.: 32

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

GnomAD2 exomes AF: 0.324 AC: 81499 AN: 251362 AF XY: 0.322

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 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.: 37 AF XY: 0.283 AC XY: 206036 AN XY: 727228

African (AFR) AF: 0.175 AC: 5864 AN: 33478

American (AMR) AF: 0.378 AC: 16885 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 8169 AN: 26136

East Asian (EAS) AF: 0.678 AC: 26913 AN: 39698

South Asian (SAS) AF: 0.333 AC: 28714 AN: 86258

European-Finnish (FIN) AF: 0.289 AC: 15419 AN: 53414

Middle Eastern (MID) AF: 0.385 AC: 2220 AN: 5768

European-Non Finnish (NFE) AF: 0.260 AC: 288654 AN: 1111962

Other (OTH) AF: 0.302 AC: 18252 AN: 60394

GnomAD4 genome AF: 0.269 AC: 40899 AN: 152146 Hom.: 6164 Cov.: 32 AF XY: 0.271 AC XY: 20184 AN XY: 74374

African (AFR) AF: 0.176 AC: 7318 AN: 41532

American (AMR) AF: 0.328 AC: 5006 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1089 AN: 3464

East Asian (EAS) AF: 0.690 AC: 3557 AN: 5152

South Asian (SAS) AF: 0.341 AC: 1648 AN: 4828

European-Finnish (FIN) AF: 0.289 AC: 3054 AN: 10580

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18229 AN: 67990

Other (OTH) AF: 0.334 AC: 704 AN: 2110

Alfa AF: 0.276 Hom.: 26003

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
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4754; hg19: chr4-88902692; COSMIC: COSV52951693; COSMIC: COSV52951693;