rs983345752

Positions:

• chr7-128997457-T-A
• chr7-128997457-T-C
• chr7-128997457-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000265388.10(TNPO3):​c.1090A>T​(p.Ile364Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I364L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNPO3 ENST00000265388.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.44

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 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=0.41123965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNPO3	NM_012470.4	c.1090A>T	p.Ile364Phe	missense_variant	8/23	ENST00000265388.10	NP_036602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNPO3	ENST00000265388.10	c.1090A>T	p.Ile364Phe	missense_variant	8/23	1	NM_012470.4	ENSP00000265388	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.092	T;T;T;.;T
Eigen	Benign	-0.080
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D;D;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N;.;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.21	T;.;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.059	B;P;.;.;P
Vest4		0.64
MutPred		0.33		Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		0.64
MPC		0.90
ClinPred		0.59	D
GERP RS		5.6
Varity_R		0.47
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs983345752; hg19: chr7-128637511;