7-128974936-G-A

Variant names:

• chr7-128974936-G-A
• rs2293493
• NM_012470.4:c.2205C>T

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.2205C>T​(p.Leu735Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0472 in 1,613,834 control chromosomes in the GnomAD database, including 2,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (201 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2032 hom.)
• Consequence: TNPO3 NM_012470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.981
• Publications: 12 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=-0.37).
• BP6: Variant 7-128974936-G-A is Benign according to our data. Variant chr7-128974936-G-A is described in ClinVar as Benign. ClinVar VariationId is 260262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.981 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0768 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.2205C>T	p.Leu735Leu	synonymous	Exon 18 of 23	NP_036602.1	Q9Y5L0-2
	TNPO3	NM_001382216.1		c.2307C>T	p.Leu769Leu	synonymous	Exon 18 of 23	NP_001369145.1	C9J7E5
	TNPO3	NM_001382217.1		c.2286C>T	p.Leu762Leu	synonymous	Exon 19 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.2205C>T	p.Leu735Leu	synonymous	Exon 18 of 23	ENSP00000265388.5	Q9Y5L0-2
	TNPO3	ENST00000471234.5	TSL:1	c.2013C>T	p.Leu671Leu	synonymous	Exon 17 of 22	ENSP00000418646.1	Q9Y5L0-5
	TNPO3	ENST00000482320.5	TSL:1	c.2007C>T	p.Leu669Leu	synonymous	Exon 19 of 24	ENSP00000420089.1	E9PFH4

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6320 AN: 152136 Hom.: 200 Cov.: 32

Gnomad AFR AF: 0.00784

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.0835

Gnomad SAS AF: 0.0709

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0514 AC: 12937 AN: 251454 AF XY: 0.0540

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0341

Gnomad EAS exome AF: 0.0809

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0477

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0478 AC: 69838 AN: 1461580 Hom.: 2032 Cov.: 30 AF XY: 0.0488 AC XY: 35449 AN XY: 727118

African (AFR) AF: 0.00747 AC: 250 AN: 33478

American (AMR) AF: 0.0207 AC: 926 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 882 AN: 26136

East Asian (EAS) AF: 0.0786 AC: 3118 AN: 39694

South Asian (SAS) AF: 0.0760 AC: 6550 AN: 86236

European-Finnish (FIN) AF: 0.0991 AC: 5295 AN: 53414

Middle Eastern (MID) AF: 0.0531 AC: 306 AN: 5764

European-Non Finnish (NFE) AF: 0.0447 AC: 49677 AN: 1111752

Other (OTH) AF: 0.0469 AC: 2834 AN: 60384

GnomAD4 genome AF: 0.0415 AC: 6319 AN: 152254 Hom.: 201 Cov.: 32 AF XY: 0.0455 AC XY: 3387 AN XY: 74438

African (AFR) AF: 0.00782 AC: 325 AN: 41566

American (AMR) AF: 0.0328 AC: 502 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 123 AN: 3472

East Asian (EAS) AF: 0.0833 AC: 431 AN: 5176

South Asian (SAS) AF: 0.0716 AC: 345 AN: 4818

European-Finnish (FIN) AF: 0.113 AC: 1199 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0479 AC: 3256 AN: 68026

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0402 Hom.: 66

Bravo AF: 0.0326

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	-0.37
CADD	Benign	6.0
DANN	Benign	0.79
PhyloP100		0.98
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: rs2293493; hg19: chr7-128614990; COSMIC: COSV55285534; COSMIC: COSV55285534;