rs12507099

Positions:

• chr4-78911552-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198892.2(BMP2K):​c.3005C>G​(p.Thr1002Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0925 in 1,613,972 control chromosomes in the GnomAD database, including 8,220 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.079 (696 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7524 hom.)
• Consequence: BMP2K NM_198892.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.34

Genes affected

BMP2K (HGNC:18041): (BMP2 inducible kinase) This gene is the human homolog of mouse BMP-2-inducible kinase. Bone morphogenic proteins (BMPs) play a key role in skeletal development and patterning. Expression of the mouse gene is increased during BMP-2 induced differentiation and the gene product is a putative serine/threonine protein kinase containing a nuclear localization signal. Therefore, the protein encoded by this human homolog is thought to be a protein kinase with a putative regulatory role in attenuating the program of osteoblast differentiation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PAQR3 (HGNC:30130): (progestin and adipoQ receptor family member 3) This gene encodes a seven-transmembrane protein localized in the Golgi apparatus in mammalian cells. The encoded protein belongs to the progestin and adipoQ receptor (PAQR) family. This protein functions as a tumor suppressor by inhibiting the Raf/MEK/ERK signaling cascade. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016516745).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP2K	NM_198892.2	c.3005C>G	p.Thr1002Ser	missense_variant	16/16	ENST00000502613.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP2K	ENST00000502613.3	c.3005C>G	p.Thr1002Ser	missense_variant	16/16	1	NM_198892.2	P1
PAQR3	ENST00000342820.10	c.*782+3658G>C		intron_variant, NMD_transcript_variant		1
PAQR3	ENST00000512760.5	c.*792+3658G>C		intron_variant, NMD_transcript_variant		1
PAQR3	ENST00000511594.5	c.*637G>C		3_prime_UTR_variant, NMD_transcript_variant	8/8	5

Frequencies

GnomAD3 genomes AF: 0.0796 AC: 12107 AN: 152168 Hom.: 697 Cov.: 32

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.0809

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0900

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.108 AC: 26768 AN: 248930 Hom.: 1844 AF XY: 0.105 AC XY: 14142 AN XY: 135056

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.245

Gnomad SAS exome AF: 0.0748

Gnomad FIN exome AF: 0.0597

Gnomad NFE exome AF: 0.0912

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0939 AC: 137243 AN: 1461686 Hom.: 7524 Cov.: 32 AF XY: 0.0928 AC XY: 67448 AN XY: 727120

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.0753

Gnomad4 FIN exome AF: 0.0610

Gnomad4 NFE exome AF: 0.0892

Gnomad4 OTH exome AF: 0.0936

GnomAD4 genome AF: 0.0795 AC: 12104 AN: 152286 Hom.: 696 Cov.: 32 AF XY: 0.0805 AC XY: 5997 AN XY: 74452

Gnomad4 AFR AF: 0.0174

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.257

Gnomad4 SAS AF: 0.0822

Gnomad4 FIN AF: 0.0573

Gnomad4 NFE AF: 0.0900

Gnomad4 OTH AF: 0.0978

Alfa AF: 0.0907 Hom.: 232

Bravo AF: 0.0852

TwinsUK AF: 0.0863 AC: 320

ALSPAC AF: 0.0867 AC: 334

ESP6500AA AF: 0.0160 AC: 62

ESP6500EA AF: 0.0929 AC: 770

ExAC AF: 0.102 AC: 12285

Asia WGS AF: 0.119 AC: 413 AN: 3478

EpiCase AF: 0.0959

EpiControl AF: 0.0948

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	T
Eigen	Benign	0.023
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.00078	P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.10
Sift	Benign	0.084	T
Sift4G	Benign	0.68	T
Polyphen		0.64	P
Vest4		0.17
MutPred		0.16		Gain of glycosylation at T1002 (P = 0.0095);
MPC		0.11
ClinPred		0.0085	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.11

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12507099; hg19: chr4-79832706; COSMIC: COSV55008799; COSMIC: COSV55008799;