rs1554435157

Variant names:

• chr7-128970203-T-C
• rs1554435157
• NM_012470.4:c.2543A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09
• Publications: 0 publications found

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

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	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	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.49
Sift	Benign	0.057	T
Sift4G	Benign	0.069	T
Polyphen		0.59	P
Vest4		0.81
MutPred		0.48		Gain of catalytic residue at P881 (P = 0.0175)
MVP		0.72
MPC		0.80
ClinPred		0.98	D
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

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

Other links and lift over

dbSNP: rs1554435157; hg19: chr7-128610257;