rs2305324

Variant names:

• chr7-129001172-G-C
• rs2305324
• NM_012470.4:c.759C>G
• TNPO3 p.Leu253Leu

Your query was ambiguous. Multiple possible variants found:

• chr7-129001172-G-C
• chr7-129001172-G-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.759C>G​(p.Leu253Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 1,613,508 control chromosomes in the GnomAD database, including 157,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11264 hom., cov: 31)
  • Exomes 𝑓: 0.44 (146369 hom.)
• Consequence: TNPO3 NM_012470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0460
• Publications: 31 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 7-129001172-G-C is Benign according to our data. Variant chr7-129001172-G-C is described in ClinVar as Benign. ClinVar VariationId is 260268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.046 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.45 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.759C>G	p.Leu253Leu	synonymous	Exon 6 of 23	NP_036602.1	Q9Y5L0-2
	TNPO3	NM_001382216.1		c.759C>G	p.Leu253Leu	synonymous	Exon 6 of 23	NP_001369145.1	C9J7E5
	TNPO3	NM_001382217.1		c.840C>G	p.Leu280Leu	synonymous	Exon 7 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.759C>G	p.Leu253Leu	synonymous	Exon 6 of 23	ENSP00000265388.5	Q9Y5L0-2
	TNPO3	ENST00000471234.5	TSL:1	c.759C>G	p.Leu253Leu	synonymous	Exon 6 of 22	ENSP00000418646.1	Q9Y5L0-5
	TNPO3	ENST00000482320.5	TSL:1	c.561C>G	p.Leu187Leu	synonymous	Exon 7 of 24	ENSP00000420089.1	E9PFH4

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55022 AN: 151766 Hom.: 11266 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.436

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.397

GnomAD2 exomes AF: 0.408 AC: 102549 AN: 251434 AF XY: 0.417

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.530

Gnomad EAS exome AF: 0.433

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.460

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.443 AC: 647149 AN: 1461622 Hom.: 146369 Cov.: 44 AF XY: 0.444 AC XY: 322988 AN XY: 727092

African (AFR) AF: 0.164 AC: 5503 AN: 33476

American (AMR) AF: 0.283 AC: 12637 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 13956 AN: 26134

East Asian (EAS) AF: 0.388 AC: 15399 AN: 39696

South Asian (SAS) AF: 0.417 AC: 35940 AN: 86238

European-Finnish (FIN) AF: 0.432 AC: 23086 AN: 53412

Middle Eastern (MID) AF: 0.440 AC: 2537 AN: 5768

European-Non Finnish (NFE) AF: 0.460 AC: 511811 AN: 1111788

Other (OTH) AF: 0.435 AC: 26280 AN: 60388

GnomAD4 genome AF: 0.362 AC: 55033 AN: 151886 Hom.: 11264 Cov.: 31 AF XY: 0.362 AC XY: 26883 AN XY: 74240

African (AFR) AF: 0.170 AC: 7046 AN: 41438

American (AMR) AF: 0.336 AC: 5126 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1875 AN: 3468

East Asian (EAS) AF: 0.407 AC: 2101 AN: 5156

South Asian (SAS) AF: 0.421 AC: 2024 AN: 4808

European-Finnish (FIN) AF: 0.433 AC: 4550 AN: 10504

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.454 AC: 30828 AN: 67924

Other (OTH) AF: 0.397 AC: 836 AN: 2108

Alfa AF: 0.432 Hom.: 4863

Bravo AF: 0.349

Asia WGS AF: 0.391 AC: 1361 AN: 3478

EpiCase AF: 0.457

EpiControl AF: 0.465

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal dominant limb-girdle muscular dystrophy type 1F (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.1
DANN	Benign	0.77
PhyloP100		-0.046
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2305324;

hg19: chr7-128641226;

COSMIC: COSV55284843;