8-144440024-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_013432.5(TONSL):c.1477G>A(p.Gly493Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,224,910 control chromosomes in the GnomAD database, including 167,745 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.54 ( 22161 hom., cov: 34)

Exomes 𝑓: 0.52 ( 145584 hom. )

Consequence

TONSL
NM_013432.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.812

Variant links:

Genes affected

TONSL (HGNC:7801): (tonsoku like, DNA repair protein) The protein encoded by this gene is thought to be a negative regulator of NF-kappa-B mediated transcription. The encoded protein may bind NF-kappa-B complexes and trap them in the cytoplasm, preventing them from entering the nucleus and interacting with the DNA. Phosphorylation of this protein targets it for degradation by the ubiquitination pathway, which frees the NF-kappa-B complexes to enter the nucleus. [provided by RefSeq, Jul 2008]

TONSL links:

TONSL-AS1 (HGNC:51556): (TONSL antisense RNA 1)

TONSL-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_013432.5

BP4

Computational evidence support a benign effect (MetaRNN=9.515272E-6).

BP6

Variant 8-144440024-C-T is Benign according to our data. Variant chr8-144440024-C-T is described in ClinVar as [Benign]. Clinvar id is 1167022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5 link	c.1477G>A	p.Gly493Ser	missense_variant	Exon 11 of 26	ENST00000409379.8	NP_038460.4	Q96HA7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TONSL	ENST00000409379.8 link	c.1477G>A	p.Gly493Ser	missense_variant	Exon 11 of 26	1	NM_013432.5	ENSP00000386239.3	Q96HA7-1
TONSL	ENST00000497613.2 link	n.2452G>A		non_coding_transcript_exon_variant	Exon 3 of 17	2
TONSL-AS1	ENST00000442850.1 link	n.*53C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.537

AC:

81685

AN:

152012

Hom.:

22144

Cov.:

show subpopulations

Gnomad AFR

AF:

0.587

Gnomad AMI

AF:

0.485

Gnomad AMR

AF:

0.509

Gnomad ASJ

AF:

0.667

Gnomad EAS

AF:

0.391

Gnomad SAS

AF:

0.409

Gnomad FIN

AF:

0.520

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.530

Gnomad OTH

AF:

0.529

GnomAD2 exomes

AF:

0.503

AC:

121897

AN:

242106

AF XY:

0.503

show subpopulations

Gnomad AFR exome

AF:

0.581

Gnomad AMR exome

AF:

0.465

Gnomad ASJ exome

AF:

0.665

Gnomad EAS exome

AF:

0.371

Gnomad FIN exome

AF:

0.517

Gnomad NFE exome

AF:

0.530

Gnomad OTH exome

AF:

0.524

GnomAD4 exome

AF:

0.517

AC:

554447

AN:

1072780

Hom.:

145584

Cov.:

AF XY:

0.514

AC XY:

283214

AN XY:

550800

show subpopulations

Gnomad4 AFR exome

AF:

0.589

AC:

15334

AN:

26028

Gnomad4 AMR exome

AF:

0.472

AC:

20406

AN:

43206

Gnomad4 ASJ exome

AF:

0.661

AC:

15630

AN:

23648

Gnomad4 EAS exome

AF:

0.395

AC:

15042

AN:

38040

Gnomad4 SAS exome

AF:

0.424

AC:

33270

AN:

78394

Gnomad4 FIN exome

AF:

0.516

AC:

26773

AN:

51848

Gnomad4 NFE exome

AF:

0.526

AC:

399420

AN:

759062

Gnomad4 Remaining exome

AF:

0.534

AC:

25404

AN:

47576

Heterozygous variant carriers

13500

27000

40501

54001

67501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

9388

18776

28164

37552

46940

<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:

0.537

AC:

81752

AN:

152130

Hom.:

22161

Cov.:

AF XY:

0.535

AC XY:

39770

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.587

AC:

0.587151

AN:

0.587151

Gnomad4 AMR

AF:

0.508

AC:

0.507786

AN:

0.507786

Gnomad4 ASJ

AF:

0.667

AC:

0.667436

AN:

0.667436

Gnomad4 EAS

AF:

0.390

AC:

0.39048

AN:

0.39048

Gnomad4 SAS

AF:

0.409

AC:

0.409374

AN:

0.409374

Gnomad4 FIN

AF:

0.520

AC:

0.519819

AN:

0.519819

Gnomad4 NFE

AF:

0.530

AC:

0.530498

AN:

0.530498

Gnomad4 OTH

AF:

0.529

AC:

0.52944

AN:

0.52944

Heterozygous variant carriers

1967

3934

5900

7867

9834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<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:

0.532

Hom.:

42851

Bravo

AF:

0.540

TwinsUK

AF:

0.517

AC:

1918

ALSPAC

AF:

0.511

AC:

1968

ESP6500AA

AF:

0.578

AC:

2541

ESP6500EA

AF:

0.535

AC:

4593

ExAC

AF:

0.502

AC:

60677

Asia WGS

AF:

0.423

AC:

1474

AN:

3478

EpiCase

AF:

0.534

EpiControl

AF:

0.536

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 13, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sponastrime dysplasia

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.74

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.11

MetaRNN

Benign

0.0000095

Sift4G

Benign

0.31

Vest4

0.032

ClinPred

0.0033

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

Mutation Taster

=96/4

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over