rs7435825

Positions:

• chr4-87982622-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001040058.2(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.043 (488 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (430 hom.)
• Consequence: SPP1 NM_001040058.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPP1	NM_001040058.2	c.671G>A	p.Ser224Asn	missense_variant	7/7	ENST00000395080.8	NP_001035147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPP1	ENST00000395080.8	c.671G>A	p.Ser224Asn	missense_variant	7/7	1	NM_001040058.2	ENSP00000378517.3

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

GnomAD3 exomes AF: 0.0116 AC: 2910 AN: 251480 Hom.: 189 AF XY: 0.00834 AC XY: 1133 AN XY: 135912

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 SAS exome AF: 0.000163

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

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.00928

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000264

Gnomad4 OTH exome AF: 0.0102

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

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.00853 Hom.: 155

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 v4.3

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;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.64	T;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;.;M;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.6	.;D;D;N;D
REVEL	Benign	0.087
Sift	Uncertain	0.014	.;D;D;D;D
Sift4G	Uncertain	0.0060	D;T;D;D;T
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

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

Other links and lift over

dbSNP: rs7435825; hg19: chr4-88903774;