Variant 5-72861900-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_002270.4(TNPO1):c.448T>C(p.Tyr150His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TNPO1
NM_002270.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

Variant links:

Genes affected

TNPO1 (HGNC:6401): (transportin 1) This gene encodes the beta subunit of the karyopherin receptor complex which interacts with nuclear localization signals to target nuclear proteins to the nucleus. The karyopherin receptor complex is a heterodimer of an alpha subunit which recognizes the nuclear localization signal and a beta subunit which docks the complex at nucleoporins. Alternate splicing of this gene results in several transcript variants encoding different proteins. [provided by RefSeq, Jun 2018]

TNPO1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TNPO1. . Gene score misZ 4.3261 (greater than the threshold 3.09). Trascript score misZ 4.9328 (greater than threshold 3.09). GenCC has associacion of gene with Tourette syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNPO1	NM_002270.4 linkuse as main transcript	c.448T>C	p.Tyr150His	missense_variant	5/25	ENST00000337273.10	NP_002261.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNPO1	ENST00000337273.10 linkuse as main transcript	c.448T>C	p.Tyr150His	missense_variant	5/25	1	NM_002270.4	ENSP00000336712		Q92973-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457982

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725590

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2023

The c.448T>C (p.Y150H) alteration is located in exon 5 (coding exon 5) of the TNPO1 gene. This alteration results from a T to C substitution at nucleotide position 448, causing the tyrosine (Y) at amino acid position 150 to be replaced by a histidine (H). 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

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.077

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Uncertain

-0.10

MutationAssessor

Pathogenic

3.1

M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Uncertain

0.40

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.023

B;P;.

Vest4

0.74

MutPred

0.39

Gain of disorder (P = 0.0231);.;.;

MVP

0.70

MPC

1.3

ClinPred

0.95

GERP RS

5.8

Varity_R

0.52

gMVP

0.54

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over