rs2853749

Variant names:

• chr4-87976662-C-T
• rs2853749
• NM_001040058.2:c.-14-220C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001040058.2(SPP1):​c.-14-220C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 151,926 control chromosomes in the GnomAD database, including 8,707 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (8707 hom., cov: 32)
• Consequence: SPP1 NM_001040058.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.63
• Publications: 15 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

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.-14-220C>T		intron	N/A	NP_001035147.1	P10451-1
	SPP1	NM_001251830.2		c.-164-220C>T		intron	N/A	NP_001238759.1	B7Z351
	SPP1	NM_000582.3		c.-14-220C>T		intron	N/A	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.-14-220C>T		intron	N/A	ENSP00000378517.3	P10451-1
	SPP1	ENST00000237623.11	TSL:1	c.-14-220C>T		intron	N/A	ENSP00000237623.7	P10451-5
	SPP1	ENST00000360804.4	TSL:1	c.-14-220C>T		intron	N/A	ENSP00000354042.4	P10451-3

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50550 AN: 151810 Hom.: 8699 Cov.: 32

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.311

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.327

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.333 AC: 50586 AN: 151926 Hom.: 8707 Cov.: 32 AF XY: 0.334 AC XY: 24789 AN XY: 74224

African (AFR) AF: 0.412 AC: 17085 AN: 41436

American (AMR) AF: 0.268 AC: 4091 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1002 AN: 3460

East Asian (EAS) AF: 0.368 AC: 1904 AN: 5168

South Asian (SAS) AF: 0.255 AC: 1228 AN: 4818

European-Finnish (FIN) AF: 0.366 AC: 3857 AN: 10534

Middle Eastern (MID) AF: 0.314 AC: 91 AN: 290

European-Non Finnish (NFE) AF: 0.298 AC: 20267 AN: 67942

Other (OTH) AF: 0.327 AC: 689 AN: 2106

Alfa AF: 0.324 Hom.: 1066

Bravo AF: 0.328

Asia WGS AF: 0.297 AC: 1025 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.31
DANN	Benign	0.16
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2853749;

hg19: chr4-88897814;