19-12703710-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001382241.1(TNPO2):c.2110+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,607,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: TNPO2 NM_001382241.1 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0002194
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.84

Genes affected

TNPO2 (HGNC:19998): (transportin 2) Predicted to enable nuclear import signal receptor activity and nuclear localization sequence binding activity. Predicted to be involved in protein import into nucleus. Predicted to act upstream of or within negative regulation of muscle cell differentiation. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SNORD135 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-12703710-G-A is Benign according to our data. Variant chr19-12703710-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3045082.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNPO2	NM_001382241.1	c.2110+4C>T		splice_donor_region_variant, intron_variant		ENST00000425528.6
SNORD135	NR_132756.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNPO2	ENST00000425528.6	c.2110+4C>T		splice_donor_region_variant, intron_variant		5	NM_001382241.1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000127 AC: 30 AN: 236808 Hom.: 0 AF XY: 0.000109 AC XY: 14 AN XY: 128488

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.0000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000116

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000281

Gnomad OTH exome AF: 0.000514

GnomAD4 exome AF: 0.0000763 AC: 111 AN: 1454792 Hom.: 0 Cov.: 31 AF XY: 0.0000774 AC XY: 56 AN XY: 723124

Gnomad4 AFR exome AF: 0.00192

Gnomad4 AMR exome AF: 0.0000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000761

Gnomad4 SAS exome AF: 0.0000352

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74464

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.000442

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TNPO2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2022

This variant is classified as likely 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	-0.84
Cadd	Benign	0.40
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.026
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

Publications

LitVar

Other links and lift over

dbSNP: rs150636988; hg19: chr19-12814524;