19-12703765-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001382241.1(TNPO2):c.2059C>T(p.Leu687Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L687I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNPO2 NM_001382241.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11

Genes affected

TNPO2 (HGNC:19998): (transportin 2) Predicted to enable nuclear import signal receptor activity and nuclear localization sequence binding activity. Predicted to be involved in protein import into nucleus. Predicted to act upstream of or within negative regulation of muscle cell differentiation. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TNPO2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNPO2	NM_001382241.1	c.2059C>T	p.Leu687Phe	missense_variant	19/26	ENST00000425528.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNPO2	ENST00000425528.6	c.2059C>T	p.Leu687Phe	missense_variant	19/26	5	NM_001382241.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Apr 20, 2022

_x000D_ Criteria applied: PM2_SUP, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;.;.;T;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;.;.;.;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.5	H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D;D;D;.;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0050	D;D;D;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;.;.;D;.
Vest4		0.71
MutPred		0.69		Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);Loss of stability (P = 0.0268);
MVP		0.35
MPC		2.7
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-12814579;