19-12706221-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM2 PP2 PP3 PP5_Moderate

The NM_001382241.1(TNPO2):c.1643C>T(p.Ser548Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNPO2 NM_001382241.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.57

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 Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_001382241.1 (TNPO2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TNPO2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793
• PP5: Variant 19-12706221-G-A is Pathogenic according to our data. Variant chr19-12706221-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1690646.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-12706221-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNPO2	NM_001382241.1	c.1643C>T	p.Ser548Phe	missense_variant	15/26	ENST00000425528.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNPO2	ENST00000425528.6	c.1643C>T	p.Ser548Phe	missense_variant	15/26	5	NM_001382241.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Feb 03, 2022

This variant has been previously published in a different individual (PMID: 34314705). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;.;T;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;.;.;.;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.2	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.6	D;D;D;.;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Benign	0.068	T;T;T;T;T
Polyphen		1.0	D;.;.;D;.
Vest4		0.83
MutPred		0.56		Loss of disorder (P = 0.0304);Loss of disorder (P = 0.0304);Loss of disorder (P = 0.0304);Loss of disorder (P = 0.0304);Loss of disorder (P = 0.0304);
MVP		0.53
MPC		2.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.83

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: chr19-12817035; COSMIC: COSV100790327; COSMIC: COSV100790327;