chr4-87981496-G-A

Variant names:

• chr4-87981496-G-A
• rs376158660
• NM_001040058.2:c.238G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001040058.2(SPP1):​c.238G>A​(p.Glu80Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: SPP1 NM_001040058.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.42
• Publications: 0 publications found

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]

SPP1 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286618 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013876885).
• BP6: Variant 4-87981496-G-A is Benign according to our data. Variant chr4-87981496-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 782812.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040058.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPP1	NM_001040058.2	MANE Select	c.238G>A	p.Glu80Lys	missense	Exon 6 of 7	NP_001035147.1	P10451-1
	SPP1	NM_001251830.2		c.277G>A	p.Glu93Lys	missense	Exon 7 of 8	NP_001238759.1	B7Z351
	SPP1	NM_000582.3		c.196G>A	p.Glu66Lys	missense	Exon 5 of 6	NP_000573.1	P10451-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPP1	ENST00000395080.8	TSL:1 MANE Select	c.238G>A	p.Glu80Lys	missense	Exon 6 of 7	ENSP00000378517.3	P10451-1
	SPP1	ENST00000237623.11	TSL:1	c.196G>A	p.Glu66Lys	missense	Exon 5 of 6	ENSP00000237623.7	P10451-5
	SPP1	ENST00000360804.4	TSL:1	c.157G>A	p.Glu53Lys	missense	Exon 5 of 6	ENSP00000354042.4	P10451-3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000276 AC: 69 AN: 250256 AF XY: 0.000273

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00343

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461712 Hom.: 0 Cov.: 30 AF XY: 0.0000523 AC XY: 38 AN XY: 727156

African (AFR) AF: 0.0000897 AC: 3 AN: 33456

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00108 AC: 43 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111914

Other (OTH) AF: 0.000248 AC: 15 AN: 60386

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74398

African (AFR) AF: 0.0000241 AC: 1 AN: 41528

American (AMR) AF: 0.000458 AC: 7 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000731 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.29
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.098	T
Polyphen		1.0	D
Vest4		0.37
MVP		0.69
MPC		0.55
ClinPred		0.13	T
GERP RS		5.6
Varity_R		0.26
gMVP		0.037
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs376158660; hg19: chr4-88902648; COSMIC: COSV52952346; COSMIC: COSV52952346;