Genetic Variant NM_012470.4:c.2543A>G (chr7-128970203-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_012470.4(TNPO3):c.2543A>G(p.Tyr848Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y848Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TNPO3
NM_012470.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.09

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.756

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012470.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNPO3	NM_012470.4	MANE Select	c.2543A>G	p.Tyr848Cys	missense	Exon 20 of 23	NP_036602.1
TNPO3	NM_001382216.1		c.2645A>G	p.Tyr882Cys	missense	Exon 20 of 23	NP_001369145.1
TNPO3	NM_001382217.1		c.2624A>G	p.Tyr875Cys	missense	Exon 21 of 24	NP_001369146.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNPO3	ENST00000265388.10	TSL:1 MANE Select	c.2543A>G	p.Tyr848Cys	missense	Exon 20 of 23	ENSP00000265388.5
TNPO3	ENST00000471234.5	TSL:1	c.2351A>G	p.Tyr784Cys	missense	Exon 19 of 22	ENSP00000418646.1
TNPO3	ENST00000482320.5	TSL:1	c.2345A>G	p.Tyr782Cys	missense	Exon 21 of 24	ENSP00000420089.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant limb-girdle muscular dystrophy type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.30

MutationAssessor

Benign

1.8

PhyloP100

6.1

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.49

Sift

Benign

0.057

Sift4G

Benign

0.069

Polyphen

0.59

Vest4

0.81

MutPred

0.48

Gain of catalytic residue at P881 (P = 0.0175)

MVP

0.72

MPC

0.80

ClinPred

0.98

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.83

gMVP

0.50

Mutation Taster

=33/67

disease causing

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over