rs1746484581

Variant names:

• chr5-72861900-T-A
• rs1746484581
• NM_002270.4:c.448T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-72861900-T-A
• chr5-72861900-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002270.4(TNPO1):​c.448T>A​(p.Tyr150Asn) 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. 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. Y150H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNPO1 NM_002270.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002270.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNPO1	NM_002270.4	MANE Select	c.448T>A	p.Tyr150Asn	missense	Exon 5 of 25	NP_002261.3
	TNPO1	NM_001364292.3		c.424T>A	p.Tyr142Asn	missense	Exon 5 of 25	NP_001351221.1	Q92973-2
	TNPO1	NM_001364293.3		c.424T>A	p.Tyr142Asn	missense	Exon 5 of 25	NP_001351222.1	Q92973-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNPO1	ENST00000337273.10	TSL:1 MANE Select	c.448T>A	p.Tyr150Asn	missense	Exon 5 of 25	ENSP00000336712.5	Q92973-1
	TNPO1	ENST00000506351.6	TSL:1	c.424T>A	p.Tyr142Asn	missense	Exon 5 of 25	ENSP00000425118.2	Q92973-2
	TNPO1	ENST00000944758.1		c.514T>A	p.Tyr172Asn	missense	Exon 5 of 25	ENSP00000614817.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.44
Sift	Benign	0.10	T
Sift4G	Benign	0.40	T
Polyphen		0.0030	B
Vest4		0.84
MutPred		0.40		Gain of disorder (P = 0.0155)
MVP		0.76
MPC		1.6
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.75
gMVP		0.70
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1746484581; hg19: chr5-72157727;