rs2293493

chr7-128974936-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_012470.4(TNPO3):c.2205C>T(p.Leu735=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0472 in 1,613,834 control chromosomes in the GnomAD database, including 2,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (201 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2032 hom.)
• Consequence: TNPO3 NM_012470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.981

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=-0.37).
• BP6: Variant 7-128974936-G-A is Benign according to our data. Variant chr7-128974936-G-A is described in ClinVar as [Benign]. Clinvar id is 260262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128974936-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.981 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNPO3	NM_012470.4	c.2205C>T	p.Leu735=	synonymous_variant	18/23	ENST00000265388.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNPO3	ENST00000265388.10	c.2205C>T	p.Leu735=	synonymous_variant	18/23	1	NM_012470.4	P1

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6320 AN: 152136 Hom.: 200 Cov.: 32

Gnomad AFR AF: 0.00784

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.0835

Gnomad SAS AF: 0.0709

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0514 AC: 12937 AN: 251454 Hom.: 433 AF XY: 0.0540 AC XY: 7343 AN XY: 135900

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0341

Gnomad EAS exome AF: 0.0809

Gnomad SAS exome AF: 0.0743

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0477

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0478 AC: 69838 AN: 1461580 Hom.: 2032 Cov.: 30 AF XY: 0.0488 AC XY: 35449 AN XY: 727118

Gnomad4 AFR exome AF: 0.00747

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0337

Gnomad4 EAS exome AF: 0.0786

Gnomad4 SAS exome AF: 0.0760

Gnomad4 FIN exome AF: 0.0991

Gnomad4 NFE exome AF: 0.0447

Gnomad4 OTH exome AF: 0.0469

GnomAD4 genome AF: 0.0415 AC: 6319 AN: 152254 Hom.: 201 Cov.: 32 AF XY: 0.0455 AC XY: 3387 AN XY: 74438

Gnomad4 AFR AF: 0.00782

Gnomad4 AMR AF: 0.0328

Gnomad4 ASJ AF: 0.0354

Gnomad4 EAS AF: 0.0833

Gnomad4 SAS AF: 0.0716

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.0479

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0404 Hom.: 66

Bravo AF: 0.0326

Asia WGS AF: 0.0900 AC: 314 AN: 3478

EpiCase AF: 0.0505

EpiControl AF: 0.0481

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2016	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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	6.0
Dann	Benign	0.79

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: rs2293493; hg19: chr7-128614990; COSMIC: COSV55285534; COSMIC: COSV55285534;