22-49961681-C-G

Variant names:

• chr22-49961681-C-G
• NM_001001852.4:c.486C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001001852.4(PIM3):​c.486C>G​(p.His162Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIM3 NM_001001852.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.520

Genes affected

PIM3 (HGNC:19310): (Pim-3 proto-oncogene, serine/threonine kinase) The protein encoded by this gene belongs to the Ser/Thr protein kinase family, and PIM subfamily. This gene is overexpressed in hematological and epithelial tumors and is associated with MYC coexpression. It plays a role in the regulation of signal transduction cascades, contributing to both cell proliferation and survival, and provides a selective advantage in tumorigenesis. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIM3	NM_001001852.4	c.486C>G	p.His162Gln	missense_variant	Exon 4 of 6	ENST00000360612.5	NP_001001852.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIM3	ENST00000360612.5	c.486C>G	p.His162Gln	missense_variant	Exon 4 of 6	1	NM_001001852.4	ENSP00000353824.4
PIM3	ENST00000467480.1	n.*35C>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.486C>G (p.H162Q) alteration is located in exon 4 (coding exon 4) of the PIM3 gene. This alteration results from a C to G substitution at nucleotide position 486, causing the histidine (H) at amino acid position 162 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.76
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.29
Sift	Benign	0.050	D
Sift4G	Benign	0.14	T
Polyphen		0.88	P
Vest4		0.29
MutPred		0.83		Gain of loop (P = 0.2045);
MVP		0.77
MPC		2.1
ClinPred		0.98	D
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.31
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr22-50355329;