Genetic Variant TNPO3:c.*746G>A (chr7-128954671-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012470.4(TNPO3):c.*746G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 151,840 control chromosomes in the GnomAD database, including 31,104 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.64 ( 31086 hom., cov: 29)

Exomes 𝑓: 0.65 ( 18 hom. )

Consequence

TNPO3
NM_012470.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.730

Publications

90 publications found

Variant links:

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

TNPO3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNPO3	NM_012470.4 link	c.*746G>A		3_prime_UTR_variant	Exon 23 of 23	ENST00000265388.10	NP_036602.1	Q9Y5L0-2A0A024R794B3KMX1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNPO3	ENST00000265388.10 link	c.*746G>A		3_prime_UTR_variant	Exon 23 of 23	1	NM_012470.4	ENSP00000265388.5		Q9Y5L0-2
TNPO3	ENST00000627585.2 link	c.*746G>A		3_prime_UTR_variant	Exon 23 of 23	2		ENSP00000487231.1		C9J7E5

Frequencies

GnomAD3 genomes

AF:

0.637

AC:

96573

AN:

151638

Hom.:

31058

Cov.:

show subpopulations

Gnomad AFR

AF:

0.593

Gnomad AMI

AF:

0.668

Gnomad AMR

AF:

0.565

Gnomad ASJ

AF:

0.754

Gnomad EAS

AF:

0.559

Gnomad SAS

AF:

0.689

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.709

Gnomad NFE

AF:

0.660

Gnomad OTH

AF:

0.648

GnomAD4 exome

AF:

0.655

AC:

AN:

Hom.:

Cov.:

AF XY:

0.661

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.667

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.637

AC:

96645

AN:

151756

Hom.:

31086

Cov.:

AF XY:

0.638

AC XY:

47298

AN XY:

74140

show subpopulations

African (AFR)

AF:

0.593

AC:

24527

AN:

41342

American (AMR)

AF:

0.564

AC:

8598

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.754

AC:

2613

AN:

3464

East Asian (EAS)

AF:

0.559

AC:

2876

AN:

5142

South Asian (SAS)

AF:

0.690

AC:

3311

AN:

4802

European-Finnish (FIN)

AF:

0.735

AC:

7745

AN:

10536

Middle Eastern (MID)

AF:

0.714

AC:

210

AN:

294

European-Non Finnish (NFE)

AF:

0.660

AC:

44802

AN:

67932

Other (OTH)

AF:

0.645

AC:

1354

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1766

3532

5298

7064

8830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

802

1604

2406

3208

4010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.651

Hom.:

41041

Bravo

AF:

0.623

Asia WGS

AF:

0.630

AC:

2193

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.9

(source)

DANN

Benign

0.68

PhyloP100

-0.73

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over