NM_001040058.2:c.64G>A

Variant names:

• chr4-87977068-G-A
• NM_001040058.2:c.64G>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.64G>A​(p.Ala22Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPP1 NM_001040058.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.190

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15350425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPP1	NM_001040058.2	c.64G>A	p.Ala22Thr	missense_variant	Exon 3 of 7	ENST00000395080.8	NP_001035147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPP1	ENST00000395080.8	c.64G>A	p.Ala22Thr	missense_variant	Exon 3 of 7	1	NM_001040058.2	ENSP00000378517.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461590 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	.;.;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.65	T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L;.;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.9	.;N;N;N;N
REVEL	Benign	0.092
Sift	Benign	0.37	.;T;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T
Polyphen		0.021	.;.;B;.;.
Vest4		0.086
MutPred		0.68		Loss of glycosylation at S24 (P = 0.0388);Loss of glycosylation at S24 (P = 0.0388);Loss of glycosylation at S24 (P = 0.0388);Loss of glycosylation at S24 (P = 0.0388);Loss of glycosylation at S24 (P = 0.0388);
MVP		0.53
MPC		0.54
ClinPred		0.10	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.038
gMVP		0.14

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: chr4-88898220;