4-78912028-C-T

Position:

• chr4-78912028-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_198892.2(BMP2K):​c.3481C>T​(p.Gln1161Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00221 in 1,601,234 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (18 hom.)
• Consequence: BMP2K NM_198892.2 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.20

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 -16 ACMG points.

• BP6: Variant 4-78912028-C-T is Benign according to our data. Variant chr4-78912028-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 218868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78912028-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00223 (3231/1448924) while in subpopulation MID AF= 0.0336 (191/5678). AF 95% confidence interval is 0.0297. There are 18 homozygotes in gnomad4_exome. There are 1724 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP2K	NM_198892.2	c.3481C>T	p.Gln1161Ter	stop_gained	16/16	ENST00000502613.3
PAQR3	NM_001040202.2	c.*8511G>A		3_prime_UTR_variant	6/6	ENST00000512733.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP2K	ENST00000502613.3	c.3481C>T	p.Gln1161Ter	stop_gained	16/16	1	NM_198892.2	P1
PAQR3	ENST00000512733.5	c.*8511G>A		3_prime_UTR_variant	6/6	1	NM_001040202.2	P1

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00309 AC: 740 AN: 239366 Hom.: 5 AF XY: 0.00329 AC XY: 426 AN XY: 129494

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.00317

Gnomad ASJ exome AF: 0.0267

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00225

Gnomad FIN exome AF: 0.000287

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.00693

GnomAD4 exome AF: 0.00223 AC: 3231 AN: 1448924 Hom.: 18 Cov.: 31 AF XY: 0.00240 AC XY: 1724 AN XY: 719330

Gnomad4 AFR exome AF: 0.000754

Gnomad4 AMR exome AF: 0.00297

Gnomad4 ASJ exome AF: 0.0255

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00214

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74476

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.0254

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.00213

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.00341 AC: 28

ExAC AF: 0.00302 AC: 365

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 24, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	0.89	D;D;D
Vest4		0.22
ClinPred		0.086	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs138262352; hg19: chr4-79833182;