chr7-128967317-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_012470.4(TNPO3):​c.2674C>A​(p.His892Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H892Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TNPO3
NM_012470.4 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.66
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TNPO3. . Gene score misZ 3.442 (greater than the threshold 3.09). Trascript score misZ 3.4155 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant limb-girdle muscular dystrophy type 1F.
BP4
Computational evidence support a benign effect (MetaRNN=0.41440818).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TNPO3NM_012470.4 linkuse as main transcriptc.2674C>A p.His892Asn missense_variant 21/23 ENST00000265388.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNPO3ENST00000265388.10 linkuse as main transcriptc.2674C>A p.His892Asn missense_variant 21/231 NM_012470.4 P1Q9Y5L0-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461596
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
727122
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1F Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 12, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 836846). This variant has not been reported in the literature in individuals affected with TNPO3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 892 of the TNPO3 protein (p.His892Asn). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Uncertain
0.033
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
22
DANN
Benign
0.88
DEOGEN2
Benign
0.034
T;T;T;.;T
Eigen
Benign
0.16
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.90
D;D;D;D;.
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.41
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.81
L;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-1.0
N;.;N;N;N
REVEL
Benign
0.19
Sift
Benign
1.0
T;.;T;T;T
Sift4G
Benign
1.0
T;T;T;T;T
Polyphen
0.0040
B;B;.;.;B
Vest4
0.72
MutPred
0.43
.;Loss of catalytic residue at K927 (P = 0.0528);.;.;Loss of catalytic residue at K927 (P = 0.0528);
MVP
0.40
MPC
0.66
ClinPred
0.51
D
GERP RS
5.8
Varity_R
0.46
gMVP
0.28

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1798015777; hg19: chr7-128607371; API