chr7-128957262-A-G

Position:

• chr7-128957262-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_012470.4(TNPO3):​c.2765T>C​(p.Phe922Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNPO3 NM_012470.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNPO3	NM_012470.4	c.2765T>C	p.Phe922Ser	missense_variant	22/23	ENST00000265388.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNPO3	ENST00000265388.10	c.2765T>C	p.Phe922Ser	missense_variant	22/23	1	NM_012470.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1F Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 12, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 922 of the TNPO3 protein (p.Phe922Ser). In 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D;D;D;.
M_CAP	Benign	0.0082	T
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.4	D;.;D;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D;.;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.95	P;P;.;.;P
Vest4		0.78
MutPred		0.56		.;Gain of phosphorylation at F956 (P = 0.0165);.;.;Gain of phosphorylation at F956 (P = 0.0165);
MVP		0.71
MPC		1.8
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.67
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-128597316;