rs11538884

Variant names:

• chr7-128972498-C-T
• rs11538884
• NM_012470.4:c.2358G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_012470.4(TNPO3):​c.2358G>A​(p.Leu786Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,613,690 control chromosomes in the GnomAD database, including 2,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (206 hom., cov: 31)
  • Exomes 𝑓: 0.048 (2036 hom.)
• Consequence: TNPO3 NM_012470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.569
• Publications: 9 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 7-128972498-C-T is Benign according to our data. Variant chr7-128972498-C-T is described in ClinVar as Benign. ClinVar VariationId is 260264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.569 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

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.2358G>A	p.Leu786Leu	synonymous	Exon 19 of 23	NP_036602.1	Q9Y5L0-2
	TNPO3	NM_001382216.1		c.2460G>A	p.Leu820Leu	synonymous	Exon 19 of 23	NP_001369145.1	C9J7E5
	TNPO3	NM_001382217.1		c.2439G>A	p.Leu813Leu	synonymous	Exon 20 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.2358G>A	p.Leu786Leu	synonymous	Exon 19 of 23	ENSP00000265388.5	Q9Y5L0-2
	TNPO3	ENST00000471234.5	TSL:1	c.2166G>A	p.Leu722Leu	synonymous	Exon 18 of 22	ENSP00000418646.1	Q9Y5L0-5
	TNPO3	ENST00000482320.5	TSL:1	c.2160G>A	p.Leu720Leu	synonymous	Exon 20 of 24	ENSP00000420089.1	E9PFH4

Frequencies

GnomAD3 genomes AF: 0.0443 AC: 6734 AN: 151842 Hom.: 205 Cov.: 31

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.0829

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.0413

GnomAD2 exomes AF: 0.0521 AC: 13101 AN: 251272 AF XY: 0.0544

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.0207

Gnomad ASJ exome AF: 0.0342

Gnomad EAS exome AF: 0.0808

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0477

Gnomad OTH exome AF: 0.0488

GnomAD4 exome AF: 0.0481 AC: 70285 AN: 1461730 Hom.: 2036 Cov.: 31 AF XY: 0.0490 AC XY: 35606 AN XY: 727154

African (AFR) AF: 0.0158 AC: 529 AN: 33474

American (AMR) AF: 0.0216 AC: 966 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 880 AN: 26134

East Asian (EAS) AF: 0.0785 AC: 3117 AN: 39692

South Asian (SAS) AF: 0.0759 AC: 6548 AN: 86234

European-Finnish (FIN) AF: 0.0990 AC: 5288 AN: 53398

Middle Eastern (MID) AF: 0.0536 AC: 309 AN: 5768

European-Non Finnish (NFE) AF: 0.0448 AC: 49769 AN: 1111928

Other (OTH) AF: 0.0477 AC: 2879 AN: 60394

GnomAD4 genome AF: 0.0443 AC: 6732 AN: 151960 Hom.: 206 Cov.: 31 AF XY: 0.0478 AC XY: 3549 AN XY: 74272

African (AFR) AF: 0.0174 AC: 723 AN: 41442

American (AMR) AF: 0.0340 AC: 519 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3468

East Asian (EAS) AF: 0.0827 AC: 427 AN: 5166

South Asian (SAS) AF: 0.0720 AC: 344 AN: 4776

European-Finnish (FIN) AF: 0.113 AC: 1197 AN: 10566

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0479 AC: 3255 AN: 67966

Other (OTH) AF: 0.0408 AC: 86 AN: 2106

Alfa AF: 0.0428 Hom.: 88

Bravo AF: 0.0360

Asia WGS AF: 0.0900 AC: 314 AN: 3478

EpiCase AF: 0.0505

EpiControl AF: 0.0481

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal dominant limb-girdle muscular dystrophy type 1F (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.7
DANN	Benign	0.82
PhyloP100		-0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs11538884; hg19: chr7-128612552;