7-128975947-A-C

Variant names:

• chr7-128975947-A-C
• rs112438598
• NM_012470.4:c.2062-12T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012470.4(TNPO3):​c.2062-12T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 1,571,134 control chromosomes in the GnomAD database, including 1,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (655 hom., cov: 32)
  • Exomes 𝑓: 0.026 (914 hom.)
• Consequence: TNPO3 NM_012470.4 intron
• Scores: Splicing: ADA: 0.003724
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.534
• Publications: 3 publications found

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]

TNPO3 Gene-Disease associations (from GenCC):

• autosomal dominant limb-girdle muscular dystrophy type 1F

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-128975947-A-C is Benign according to our data. Variant chr7-128975947-A-C is described in ClinVar as Benign. ClinVar VariationId is 260261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNPO3	NM_012470.4	c.2062-12T>G		intron_variant	Intron 16 of 22	ENST00000265388.10	NP_036602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNPO3	ENST00000265388.10	c.2062-12T>G		intron_variant	Intron 16 of 22	1	NM_012470.4	ENSP00000265388.5

Frequencies

GnomAD3 genomes AF: 0.0643 AC: 9784 AN: 152174 Hom.: 656 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0275

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0368

GnomAD2 exomes AF: 0.0279 AC: 6968 AN: 250162 AF XY: 0.0241

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.00537

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0335

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0263 AC: 37300 AN: 1418842 Hom.: 914 Cov.: 24 AF XY: 0.0250 AC XY: 17696 AN XY: 708344

African (AFR) AF: 0.173 AC: 5640 AN: 32650

American (AMR) AF: 0.0162 AC: 722 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00488 AC: 126 AN: 25846

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39424

South Asian (SAS) AF: 0.00431 AC: 367 AN: 85202

European-Finnish (FIN) AF: 0.0354 AC: 1891 AN: 53400

Middle Eastern (MID) AF: 0.0114 AC: 65 AN: 5702

European-Non Finnish (NFE) AF: 0.0250 AC: 26815 AN: 1073148

Other (OTH) AF: 0.0284 AC: 1672 AN: 58902

GnomAD4 genome AF: 0.0643 AC: 9792 AN: 152292 Hom.: 655 Cov.: 32 AF XY: 0.0622 AC XY: 4634 AN XY: 74472

African (AFR) AF: 0.174 AC: 7241 AN: 41536

American (AMR) AF: 0.0274 AC: 420 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.0342 AC: 363 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0241 AC: 1637 AN: 68030

Other (OTH) AF: 0.0365 AC: 77 AN: 2112

Alfa AF: 0.0411 Hom.: 65

Bravo AF: 0.0672

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 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	-0.80
CADD	Benign	10
DANN	Benign	0.55
PhyloP100		0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0037
dbscSNV1_RF	Benign	0.078
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: rs112438598; hg19: chr7-128616001;