4-87981679-C-A

Variant summary

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

The NM_001040058.2(SPP1):​c.421C>A​(p.Pro141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)

Consequence

SPP1
NM_001040058.2 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPP1NM_001040058.2 linkc.421C>A p.Pro141Thr missense_variant Exon 6 of 7 ENST00000395080.8 NP_001035147.1 P10451-1A0A024RDE2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPP1ENST00000395080.8 linkc.421C>A p.Pro141Thr missense_variant Exon 6 of 7 1 NM_001040058.2 ENSP00000378517.3 P10451-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 10, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.421C>A (p.P141T) alteration is located in exon 6 (coding exon 5) of the SPP1 gene. This alteration results from a C to A substitution at nucleotide position 421, causing the proline (P) at amino acid position 141 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
0.17
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
.;.;T;T;.
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.25
FATHMM_MKL
Benign
0.18
N
LIST_S2
Uncertain
0.87
D;T;T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Uncertain
0.44
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
.;.;L;.;.
PrimateAI
Benign
0.38
T
PROVEAN
Pathogenic
-5.1
.;D;D;D;D
REVEL
Benign
0.16
Sift
Benign
0.069
.;T;T;T;T
Sift4G
Benign
0.071
T;T;T;T;T
Polyphen
0.98
.;.;D;.;.
Vest4
0.72
MutPred
0.54
.;.;Loss of glycosylation at T138 (P = 0.0455);.;.;
MVP
0.75
MPC
0.59
ClinPred
0.97
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.37
gMVP
0.045

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-88902831; API