4-87982701-C-T

Variant names:

• chr4-87982701-C-T
• rs1126616
• NM_001040058.2:c.750C>T

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.750C>T​(p.Ala250Ala) 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 1,613,676 control chromosomes in the GnomAD database, including 68,736 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 (6151 hom., cov: 32)
  • Exomes 𝑓: 0.28 (62585 hom.)
• Consequence: SPP1 NM_001040058.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0980
• Publications: 81 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=-0.76).
• BP7: Synonymous conserved (PhyloP=-0.098 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPP1	NM_001040058.2	c.750C>T	p.Ala250Ala	synonymous_variant	Exon 7 of 7	ENST00000395080.8	NP_001035147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPP1	ENST00000395080.8	c.750C>T	p.Ala250Ala	synonymous_variant	Exon 7 of 7	1	NM_001040058.2	ENSP00000378517.3

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40803 AN: 151708 Hom.: 6152 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.330

GnomAD2 exomes AF: 0.324 AC: 81509 AN: 251432 AF XY: 0.322

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.707

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.281 AC: 411047 AN: 1461850 Hom.: 62585 Cov.: 36 AF XY: 0.283 AC XY: 206001 AN XY: 727230

African (AFR) AF: 0.175 AC: 5871 AN: 33480

American (AMR) AF: 0.377 AC: 16862 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 8168 AN: 26136

East Asian (EAS) AF: 0.678 AC: 26925 AN: 39700

South Asian (SAS) AF: 0.333 AC: 28682 AN: 86252

European-Finnish (FIN) AF: 0.289 AC: 15420 AN: 53418

Middle Eastern (MID) AF: 0.385 AC: 2221 AN: 5768

European-Non Finnish (NFE) AF: 0.260 AC: 288644 AN: 1111980

Other (OTH) AF: 0.302 AC: 18254 AN: 60392

GnomAD4 genome AF: 0.269 AC: 40832 AN: 151826 Hom.: 6151 Cov.: 32 AF XY: 0.271 AC XY: 20128 AN XY: 74196

African (AFR) AF: 0.176 AC: 7302 AN: 41392

American (AMR) AF: 0.328 AC: 5004 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1093 AN: 3464

East Asian (EAS) AF: 0.693 AC: 3562 AN: 5140

South Asian (SAS) AF: 0.342 AC: 1645 AN: 4808

European-Finnish (FIN) AF: 0.288 AC: 3032 AN: 10520

Middle Eastern (MID) AF: 0.411 AC: 120 AN: 292

European-Non Finnish (NFE) AF: 0.268 AC: 18197 AN: 67914

Other (OTH) AF: 0.333 AC: 703 AN: 2110

Alfa AF: 0.269 Hom.: 3985

Bravo AF: 0.274

Asia WGS AF: 0.497 AC: 1731 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	-0.76
CADD	Benign	3.7
DANN	Benign	0.64
PhyloP100		-0.098
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: rs1126616; hg19: chr4-88903853; COSMIC: COSV52951697; COSMIC: COSV52951697;