rs4660

chr4-87982853-G-Achr4-87982853-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001040058.2(SPP1):c.902G>A(p.Arg301His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,613,936 control chromosomes in the GnomAD database, including 240 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (125 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (115 hom.)
• Consequence: SPP1 NM_001040058.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.415

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002010107).
• BP6: Variant 4-87982853-G-A is Benign according to our data. Variant chr4-87982853-G-A is described in ClinVar as [Benign]. Clinvar id is 775997.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPP1	NM_001040058.2	c.902G>A	p.Arg301His	missense_variant	7/7	ENST00000395080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPP1	ENST00000395080.8	c.902G>A	p.Arg301His	missense_variant	7/7	1	NM_001040058.2	P1
	ENST00000662475.1	n.307+6505C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3361 AN: 152056 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.0759

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00878

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00636 AC: 1597 AN: 250938 Hom.: 58 AF XY: 0.00470 AC XY: 637 AN XY: 135642

Gnomad AFR exome AF: 0.0783

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000670

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00265 AC: 3873 AN: 1461762 Hom.: 115 Cov.: 32 AF XY: 0.00229 AC XY: 1664 AN XY: 727166

Gnomad4 AFR exome AF: 0.0787

Gnomad4 AMR exome AF: 0.00479

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00244

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000434

Gnomad4 OTH exome AF: 0.00502

GnomAD4 genome AF: 0.0221 AC: 3362 AN: 152174 Hom.: 125 Cov.: 32 AF XY: 0.0217 AC XY: 1615 AN XY: 74396

Gnomad4 AFR AF: 0.0758

Gnomad4 AMR AF: 0.00870

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00324 Hom.: 22

Bravo AF: 0.0250

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0769 AC: 339

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00796 AC: 966

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.84	T;T;D;T
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
Sift4G	Benign	0.55	T;T;T;T
Polyphen		0.13	.;.;B;.
Vest4		0.24
MVP		0.56
MPC		0.61
ClinPred		0.0071	T
GERP RS		0.21
Varity_R		0.036
gMVP		0.052

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: rs4660; hg19: chr4-88904005;