rs35060568

Variant names:

• chr7-128975843-C-A
• rs35060568
• NM_012470.4:c.2154G>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_012470.4(TNPO3):​c.2154G>T​(p.Arg718Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,613,618 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (53 hom.)
• Consequence: TNPO3 NM_012470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.475

Genes affected

TNPO3 (HGNC:17103): (transportin 3) The protein encoded by this gene is a nuclear import receptor for serine/arginine-rich (SR) proteins such as the splicing factors SFRS1 and SFRS2. The encoded protein has also been shown to be involved in HIV-1 infection, apparently through interaction with the HIV-1 capsid protein. Several protein-coding and non-coding transcript variants have been found for this gene. [provided by RefSeq, Apr 2020]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 7-128975843-C-A is Benign according to our data. Variant chr7-128975843-C-A is described in ClinVar as [Benign]. Clinvar id is 380944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128975843-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.475 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2051/152334) while in subpopulation AFR AF= 0.0464 (1928/41566). AF 95% confidence interval is 0.0447. There are 34 homozygotes in gnomad4. There are 967 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2051 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNPO3	NM_012470.4	c.2154G>T	p.Arg718Arg	synonymous_variant	Exon 17 of 23	ENST00000265388.10	NP_036602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNPO3	ENST00000265388.10	c.2154G>T	p.Arg718Arg	synonymous_variant	Exon 17 of 23	1	NM_012470.4	ENSP00000265388.5

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2029 AN: 152216 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00367 AC: 922 AN: 251344 Hom.: 12 AF XY: 0.00290 AC XY: 394 AN XY: 135836

Gnomad AFR exome AF: 0.0480

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00152 AC: 2227 AN: 1461284 Hom.: 53 Cov.: 30 AF XY: 0.00138 AC XY: 1002 AN XY: 726970

Gnomad4 AFR exome AF: 0.0496

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.0135 AC: 2051 AN: 152334 Hom.: 34 Cov.: 32 AF XY: 0.0130 AC XY: 967 AN XY: 74480

Gnomad4 AFR AF: 0.0464

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00771 Hom.: 11

Bravo AF: 0.0151

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Oct 31, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant limb-girdle muscular dystrophy type 1F Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	6.9
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs35060568; hg19: chr7-128615897;