dbSNP rs11640138: TNP2:p.Arg131Trp (chr16-11268872-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005425.5(TNP2):c.391C>T(p.Arg131Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 1,577,960 control chromosomes in the GnomAD database, including 209,983 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.44 ( 15797 hom., cov: 31)

Exomes 𝑓: 0.51 ( 194186 hom. )

Consequence

TNP2
NM_005425.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.13

Publications

48 publications found

Variant links:

Genes affected

TNP2 (HGNC:11952): (transition protein 2) Predicted to enable zinc ion binding activity. Predicted to be involved in positive regulation of protein processing; single fertilization; and spermatogenesis, exchange of chromosomal proteins. Predicted to act upstream of or within binding activity of sperm to zona pellucida and flagellated sperm motility. Predicted to be located in nucleus. Predicted to be part of nucleosome. [provided by Alliance of Genome Resources, Apr 2022]

TNP2 links:

RMI2 (HGNC:28349): (RecQ mediated genome instability 2) RMI2 is a component of the BLM (RECQL3; MIM 604610) complex, which plays a role in homologous recombination-dependent DNA repair and is essential for genome stability (Xu et al., 2008 [PubMed 18923082]).[supplied by OMIM, Nov 2008]

RMI2 links:

LOC105371082 (HGNC:):

LOC105371082 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4927983E-4).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNP2	NM_005425.5 link	c.391C>T	p.Arg131Trp	missense_variant	Exon 1 of 2	ENST00000312693.4	NP_005416.1	Q05952Q4VB56
LOC105371082	XR_933070.4 link	n.178+19094G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNP2	ENST00000312693.4 link	c.391C>T	p.Arg131Trp	missense_variant	Exon 1 of 2	1	NM_005425.5	ENSP00000325738.3		Q05952

Frequencies

GnomAD3 genomes

AF:

0.437

AC:

66332

AN:

151758

Hom.:

15802

Cov.:

show subpopulations

Gnomad AFR

AF:

0.283

Gnomad AMI

AF:

0.621

Gnomad AMR

AF:

0.373

Gnomad ASJ

AF:

0.412

Gnomad EAS

AF:

0.251

Gnomad SAS

AF:

0.317

Gnomad FIN

AF:

0.582

Gnomad MID

AF:

0.475

Gnomad NFE

AF:

0.543

Gnomad OTH

AF:

0.463

GnomAD2 exomes

AF:

0.437

AC:

97017

AN:

221988

AF XY:

0.444

show subpopulations

Gnomad AFR exome

AF:

0.276

Gnomad AMR exome

AF:

0.265

Gnomad ASJ exome

AF:

0.410

Gnomad EAS exome

AF:

0.247

Gnomad FIN exome

AF:

0.582

Gnomad NFE exome

AF:

0.540

Gnomad OTH exome

AF:

0.471

GnomAD4 exome

AF:

0.512

AC:

730077

AN:

1426084

Hom.:

194186

Cov.:

AF XY:

0.507

AC XY:

358308

AN XY:

706452

show subpopulations

African (AFR)

AF:

0.268

AC:

8505

AN:

31708

American (AMR)

AF:

0.280

AC:

10931

AN:

39060

Ashkenazi Jewish (ASJ)

AF:

0.413

AC:

9960

AN:

24102

East Asian (EAS)

AF:

0.229

AC:

9024

AN:

39422

South Asian (SAS)

AF:

0.326

AC:

26313

AN:

80634

European-Finnish (FIN)

AF:

0.585

AC:

30391

AN:

51960

Middle Eastern (MID)

AF:

0.387

AC:

2154

AN:

5570

European-Non Finnish (NFE)

AF:

0.552

AC:

604045

AN:

1094868

Other (OTH)

AF:

0.489

AC:

28754

AN:

58760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

19460

38920

58379

77839

97299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16920

33840

50760

67680

84600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.437

AC:

66311

AN:

151876

Hom.:

15797

Cov.:

AF XY:

0.433

AC XY:

32161

AN XY:

74226

show subpopulations

African (AFR)

AF:

0.283

AC:

11698

AN:

41400

American (AMR)

AF:

0.372

AC:

5669

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.412

AC:

1427

AN:

3466

East Asian (EAS)

AF:

0.251

AC:

1297

AN:

5164

South Asian (SAS)

AF:

0.316

AC:

1517

AN:

4804

European-Finnish (FIN)

AF:

0.582

AC:

6136

AN:

10536

Middle Eastern (MID)

AF:

0.466

AC:

137

AN:

294

European-Non Finnish (NFE)

AF:

0.543

AC:

36898

AN:

67954

Other (OTH)

AF:

0.459

AC:

967

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1758

3517

5275

7034

8792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

608

1216

1824

2432

3040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.493

Hom.:

72667

Bravo

AF:

0.412

TwinsUK

AF:

0.550

AC:

2041

ALSPAC

AF:

0.535

AC:

2060

ESP6500AA

AF:

0.272

AC:

1080

ESP6500EA

AF:

0.534

AC:

4437

ExAC

AF:

0.436

AC:

52744

Asia WGS

AF:

0.282

AC:

981

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.71

T;T

MetaRNN

Benign

0.00015

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

.;L

PhyloP100

2.1

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-5.5

.;D

REVEL

Benign

0.068

Sift

Benign

0.078

.;T

Sift4G

Uncertain

0.0020

.;D

Polyphen

0.89

.;P

Vest4

0.31

MPC

0.38

ClinPred

0.064

GERP RS

1.7

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.11

gMVP

0.0027

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over