NM_002270.4:c.355+8A>G

Variant names:

• chr5-72855931-A-G
• rs116204058
• NM_002270.4:c.355+8A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002270.4(TNPO1):​c.355+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,612,512 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0064 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (6 hom.)
• Consequence: TNPO1 NM_002270.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005385
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0840
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-72855931-A-G is Benign according to our data. Variant chr5-72855931-A-G is described in ClinVar as Benign. ClinVar VariationId is 3035166.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00641 (977/152366) while in subpopulation AFR AF = 0.0225 (937/41584). AF 95% confidence interval is 0.0213. There are 11 homozygotes in GnomAd4. There are 466 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.355+8A>G		splice_region intron	N/A	NP_002261.3
	TNPO1	NM_001364292.3		c.331+8A>G		splice_region intron	N/A	NP_001351221.1	Q92973-2
	TNPO1	NM_001364293.3		c.331+8A>G		splice_region intron	N/A	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.355+8A>G		splice_region intron	N/A	ENSP00000336712.5	Q92973-1
	TNPO1	ENST00000506351.6	TSL:1	c.331+8A>G		splice_region intron	N/A	ENSP00000425118.2	Q92973-2
	TNPO1	ENST00000944758.1		c.355+8A>G		splice_region intron	N/A	ENSP00000614817.1

Frequencies

GnomAD3 genomes AF: 0.00638 AC: 971 AN: 152248 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00161 AC: 402 AN: 249422 AF XY: 0.00122

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.000674

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.000615 AC: 898 AN: 1460146 Hom.: 6 Cov.: 30 AF XY: 0.000491 AC XY: 357 AN XY: 726392

African (AFR) AF: 0.0218 AC: 728 AN: 33402

American (AMR) AF: 0.000945 AC: 42 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5746

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111266

Other (OTH) AF: 0.00109 AC: 66 AN: 60332

GnomAD4 genome AF: 0.00641 AC: 977 AN: 152366 Hom.: 11 Cov.: 32 AF XY: 0.00625 AC XY: 466 AN XY: 74516

African (AFR) AF: 0.0225 AC: 937 AN: 41584

American (AMR) AF: 0.00150 AC: 23 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00323 Hom.: 5

Bravo AF: 0.00684

Asia WGS AF: 0.000866 AC: 3 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
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.51
PhyloP100		-0.084
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs116204058; hg19: chr5-72151758;