rs61756249

Variant names:

• chr7-128957286-G-A
• rs61756249
• NM_012470.4:c.2741C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-128957286-G-A
• chr7-128957286-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_012470.4(TNPO3):​c.2741C>T​(p.Ala914Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A914T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: TNPO3 NM_012470.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 9.21
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057059377).
• BP6: Variant 7-128957286-G-A is Benign according to our data. Variant chr7-128957286-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282446.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000657 (100/152316) while in subpopulation AMR AF = 0.0032 (49/15296). AF 95% confidence interval is 0.00249. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 100 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.2741C>T	p.Ala914Val	missense	Exon 22 of 23	NP_036602.1	Q9Y5L0-2
	TNPO3	NM_001382216.1		c.2843C>T	p.Ala948Val	missense	Exon 22 of 23	NP_001369145.1	C9J7E5
	TNPO3	NM_001382217.1		c.2822C>T	p.Ala941Val	missense	Exon 23 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.2741C>T	p.Ala914Val	missense	Exon 22 of 23	ENSP00000265388.5	Q9Y5L0-2
	TNPO3	ENST00000471234.5	TSL:1	c.2549C>T	p.Ala850Val	missense	Exon 21 of 22	ENSP00000418646.1	Q9Y5L0-5
	TNPO3	ENST00000482320.5	TSL:1	c.2543C>T	p.Ala848Val	missense	Exon 23 of 24	ENSP00000420089.1	E9PFH4

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000652 AC: 164 AN: 251378 AF XY: 0.000692

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000368 AC: 538 AN: 1461806 Hom.: 1 Cov.: 31 AF XY: 0.000384 AC XY: 279 AN XY: 727202

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.00172 AC: 77 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5768

European-Non Finnish (NFE) AF: 0.000237 AC: 264 AN: 1111948

Other (OTH) AF: 0.000944 AC: 57 AN: 60390

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74464

African (AFR) AF: 0.000120 AC: 5 AN: 41566

American (AMR) AF: 0.00320 AC: 49 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000501 Hom.: 0

Bravo AF: 0.000710

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Autosomal dominant limb-girdle muscular dystrophy type 1F (1)
-	-	1	TNPO3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.21
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.032	D
Polyphen		0.86	P
Vest4		0.81
MVP		0.71
MPC		0.94
ClinPred		0.060	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.66
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs61756249; hg19: chr7-128597340;