chr7-129005130-A-C

Variant names:

• chr7-129005130-A-C
• rs148885407
• NM_012470.4:c.582T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012470.4(TNPO3):​c.582T>G​(p.Asp194Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D194D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TNPO3 NM_012470.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• 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):

• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant limb-girdle muscular dystrophy type 1F

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19914818).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.582T>G	p.Asp194Glu	missense	Exon 5 of 23	NP_036602.1	Q9Y5L0-2
	TNPO3	NM_001382216.1		c.582T>G	p.Asp194Glu	missense	Exon 5 of 23	NP_001369145.1	C9J7E5
	TNPO3	NM_001382217.1		c.663T>G	p.Asp221Glu	missense	Exon 6 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.582T>G	p.Asp194Glu	missense	Exon 5 of 23	ENSP00000265388.5	Q9Y5L0-2
	TNPO3	ENST00000471234.5	TSL:1	c.582T>G	p.Asp194Glu	missense	Exon 5 of 22	ENSP00000418646.1	Q9Y5L0-5
	TNPO3	ENST00000482320.5	TSL:1	c.384T>G	p.Asp128Glu	missense	Exon 6 of 24	ENSP00000420089.1	E9PFH4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461610 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727094

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111870

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.23
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.18	B
Vest4		0.11
MutPred		0.35		Gain of disorder (P = 0.0852)
MVP		0.65
MPC		1.2
ClinPred		0.92	D
GERP RS		3.2
Varity_R		0.45
gMVP		0.49
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148885407; hg19: chr7-128645184;