rs7435825

Variant names:

• chr4-87982622-G-A
• rs7435825
• NM_001040058.2:c.671G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000395080.8(SPP1):​c.671G>A​(p.Ser224Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00824 in 1,614,054 control chromosomes in the GnomAD database, including 918 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.043 (488 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (430 hom.)
• Consequence: SPP1 ENST00000395080.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001668185).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395080.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPP1	NM_001040058.2	MANE Select	c.671G>A	p.Ser224Asn	missense	Exon 7 of 7	NP_001035147.1
	SPP1	NM_001251830.2		c.710G>A	p.Ser237Asn	missense	Exon 8 of 8	NP_001238759.1
	SPP1	NM_000582.3		c.629G>A	p.Ser210Asn	missense	Exon 6 of 6	NP_000573.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPP1	ENST00000395080.8	TSL:1 MANE Select	c.671G>A	p.Ser224Asn	missense	Exon 7 of 7	ENSP00000378517.3
	SPP1	ENST00000237623.11	TSL:1	c.629G>A	p.Ser210Asn	missense	Exon 6 of 6	ENSP00000237623.7
	SPP1	ENST00000360804.4	TSL:1	c.590G>A	p.Ser197Asn	missense	Exon 6 of 6	ENSP00000354042.4

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6597 AN: 152046 Hom.: 489 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0310

GnomAD2 exomes AF: 0.0116 AC: 2910 AN: 251480 AF XY: 0.00834

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.00789

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00458 AC: 6689 AN: 1461890 Hom.: 430 Cov.: 30 AF XY: 0.00396 AC XY: 2883 AN XY: 727246

African (AFR) AF: 0.157 AC: 5254 AN: 33480

American (AMR) AF: 0.00928 AC: 415 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00884 AC: 51 AN: 5768

European-Non Finnish (NFE) AF: 0.000264 AC: 294 AN: 1112008

Other (OTH) AF: 0.0102 AC: 619 AN: 60396

GnomAD4 genome AF: 0.0434 AC: 6608 AN: 152164 Hom.: 488 Cov.: 32 AF XY: 0.0421 AC XY: 3134 AN XY: 74398

African (AFR) AF: 0.151 AC: 6267 AN: 41492

American (AMR) AF: 0.0152 AC: 233 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68002

Other (OTH) AF: 0.0307 AC: 65 AN: 2116

Alfa AF: 0.0141 Hom.: 367

Bravo AF: 0.0497

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.143 AC: 628

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0143 AC: 1740

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.0
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.087
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.59	P
Vest4		0.049
MPC		0.11
ClinPred		0.041	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.10
Mutation Taster		=97/3	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: rs7435825; hg19: chr4-88903774;