chr5-72855931-A-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

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]

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 id 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 FAILED quality control check.
• BS2: High AC in GnomAd4 at 977 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNPO1	NM_002270.4	c.355+8A>G		splice_region_variant, intron_variant	Intron 4 of 24	ENST00000337273.10	NP_002261.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNPO1	ENST00000337273.10	c.355+8A>G		splice_region_variant, intron_variant	Intron 4 of 24	1	NM_002270.4	ENSP00000336712.5

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

Gnomad4 AFR exome AF: 0.0218 AC: 728 AN: 33402

Gnomad4 AMR exome AF: 0.000945 AC: 42 AN: 44422

Gnomad4 ASJ exome AF: 0.00165 AC: 43 AN: 26086

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39608

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85960

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53324

Gnomad4 NFE exome AF: 0.0000153 AC: 17 AN: 1111266

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.0225 AC: 0.0225327 AN: 0.0225327

Gnomad4 AMR AF: 0.00150 AC: 0.00150229 AN: 0.00150229

Gnomad4 ASJ AF: 0.00115 AC: 0.0011534 AN: 0.0011534

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000293953 AN: 0.0000293953

Gnomad4 OTH AF: 0.00473 AC: 0.00473037 AN: 0.00473037

Alfa AF: 0.00323 Hom.: 5

Bravo AF: 0.00684

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TNPO1-related disorder Benign:1

Jul 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.51
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

Publications

LitVar

Other links and lift over

dbSNP: rs116204058; hg19: chr5-72151758;