7-128977412-A-G

Variant names:

• chr7-128977412-A-G
• rs12531711
• NM_012470.4:c.2062-1477T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012470.4(TNPO3):​c.2062-1477T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0902 in 152,236 control chromosomes in the GnomAD database, including 855 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.090 (855 hom., cov: 33)
• Consequence: TNPO3 NM_012470.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 53 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNPO3	NM_012470.4	c.2062-1477T>C		intron_variant	Intron 16 of 22	ENST00000265388.10	NP_036602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNPO3	ENST00000265388.10	c.2062-1477T>C		intron_variant	Intron 16 of 22	1	NM_012470.4	ENSP00000265388.5

Frequencies

GnomAD3 genomes AF: 0.0903 AC: 13735 AN: 152118 Hom.: 858 Cov.: 33

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.102

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0902 AC: 13729 AN: 152236 Hom.: 855 Cov.: 33 AF XY: 0.0928 AC XY: 6908 AN XY: 74420

African (AFR) AF: 0.0243 AC: 1008 AN: 41564

American (AMR) AF: 0.138 AC: 2115 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5176

South Asian (SAS) AF: 0.153 AC: 736 AN: 4822

European-Finnish (FIN) AF: 0.144 AC: 1525 AN: 10590

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7657 AN: 68010

Other (OTH) AF: 0.101 AC: 213 AN: 2104

Alfa AF: 0.0967 Hom.: 2071

Bravo AF: 0.0870

Asia WGS AF: 0.0580 AC: 201 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	16
DANN	Benign	0.57
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs12531711; hg19: chr7-128617466;