4-87976916-C-G

Position:

• chr4-87976916-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001040058.2(SPP1):​c.21C>G​(p.Cys7Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPP1 NM_001040058.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

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]

ENSG00000286618 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPP1	NM_001040058.2	c.21C>G	p.Cys7Trp	missense_variant	2/7	ENST00000395080.8	NP_001035147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPP1	ENST00000395080.8	c.21C>G	p.Cys7Trp	missense_variant	2/7	1	NM_001040058.2	ENSP00000378517.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Aug 10, 2024

The c.21C>G (p.C7W) alteration is located in exon 2 (coding exon 1) of the SPP1 gene. This alteration results from a C to G substitution at nucleotide position 21, causing the cysteine (C) at amino acid position 7 to be replaced by a tryptophan (W). 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	Pathogenic	0.67
BayesDel_addAF	Benign	0.0060	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	.;.;D;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;M;M;.;M
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-9.9	.;D;D;D;D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.010	.;.;B;.;.
Vest4		0.70
MutPred		0.82		Gain of MoRF binding (P = 0.0276);Gain of MoRF binding (P = 0.0276);Gain of MoRF binding (P = 0.0276);Gain of MoRF binding (P = 0.0276);Gain of MoRF binding (P = 0.0276);
MVP		0.93
MPC		0.20
ClinPred		0.97	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr4-88898068;