NM_002270.4:c.916C>T

Variant names:

• chr5-72877342-C-T
• rs200584417
• NM_002270.4:c.916C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002270.4(TNPO1):​c.916C>T​(p.Pro306Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,556,558 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: TNPO1 NM_002270.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.19
• Publications: 3 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008200914).
• BP6: Variant 5-72877342-C-T is Benign according to our data. Variant chr5-72877342-C-T is described in ClinVar as Benign. ClinVar VariationId is 3042536.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 Unknown gene

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.916C>T	p.Pro306Ser	missense	Exon 9 of 25	NP_002261.3
	TNPO1	NM_001364292.3		c.892C>T	p.Pro298Ser	missense	Exon 9 of 25	NP_001351221.1	Q92973-2
	TNPO1	NM_001364293.3		c.892C>T	p.Pro298Ser	missense	Exon 9 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.916C>T	p.Pro306Ser	missense	Exon 9 of 25	ENSP00000336712.5	Q92973-1
	TNPO1	ENST00000506351.6	TSL:1	c.892C>T	p.Pro298Ser	missense	Exon 9 of 25	ENSP00000425118.2	Q92973-2
	TNPO1	ENST00000944758.1		c.982C>T	p.Pro328Ser	missense	Exon 9 of 25	ENSP00000614817.1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152078 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000864 AC: 214 AN: 247664 AF XY: 0.000790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000291 AC: 409 AN: 1404362 Hom.: 2 Cov.: 23 AF XY: 0.000275 AC XY: 193 AN XY: 701394

African (AFR) AF: 0.0000928 AC: 3 AN: 32342

American (AMR) AF: 0.0000228 AC: 1 AN: 43920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25380

East Asian (EAS) AF: 0.00792 AC: 311 AN: 39276

South Asian (SAS) AF: 0.000228 AC: 19 AN: 83182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00000376 AC: 4 AN: 1063738

Other (OTH) AF: 0.00122 AC: 71 AN: 58096

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152196 Hom.: 0 Cov.: 31 AF XY: 0.000322 AC XY: 24 AN XY: 74420

African (AFR) AF: 0.00 AC: 0 AN: 41516

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000413 Hom.: 0

Bravo AF: 0.000521

ExAC AF: 0.000642 AC: 78

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TNPO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.31	N
PhyloP100		1.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.097
Sift	Benign	0.42	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.35
MPC		1.0
ClinPred		0.035	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.10
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs200584417; hg19: chr5-72173169; COSMIC: COSV61522590; COSMIC: COSV61522590;