4-87980121-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040058.2(SPP1):c.169C>A(p.Pro57Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SPP1 NM_001040058.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.656

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2223945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPP1	NM_001040058.2	c.169C>A	p.Pro57Thr	missense_variant	4/7	ENST00000395080.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPP1	ENST00000395080.8	c.169C>A	p.Pro57Thr	missense_variant	4/7	1	NM_001040058.2	P1
	ENST00000662475.1	n.308-4259G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251378 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461850 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

The c.169C>A (p.P57T) alteration is located in exon 4 (coding exon 3) of the SPP1 gene. This alteration results from a C to A substitution at nucleotide position 169, causing the proline (P) at amino acid position 57 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.0082
Eigen_PC	Benign	0.0011
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;M
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.78	.;.;P
Vest4		0.16
MutPred		0.49		Gain of glycosylation at S62 (P = 0.0286);Gain of glycosylation at S62 (P = 0.0286);Gain of glycosylation at S62 (P = 0.0286);
MVP		0.81
MPC		0.53
ClinPred		0.77	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.13

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: rs1011223303; hg19: chr4-88901273;