8-144440039-C-T

Position:

chr8-144440039-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_013432.5(TONSL):c.1462G>A(p.Val488Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,404,268 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.019 ( 100 hom., cov: 34)

Exomes 𝑓: 0.0019 ( 86 hom. )

Consequence

TONSL
NM_013432.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.07

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 (HGNC:):

TONSL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026845336).

BP6

Variant 8-144440039-C-T is Benign according to our data. Variant chr8-144440039-C-T is described in ClinVar as [Benign]. Clinvar id is 716094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TONSL	NM_013432.5 linkuse as main transcript	c.1462G>A	p.Val488Met	missense_variant	11/26	ENST00000409379.8	NP_038460.4	Q96HA7-1
TONSL	XM_011517048.3 linkuse as main transcript	c.490G>A	p.Val164Met	missense_variant	4/19		XP_011515350.1
TONSL	XM_011517049.3 linkuse as main transcript	c.454G>A	p.Val152Met	missense_variant	4/19		XP_011515351.1
TONSL	XM_011517050.3 linkuse as main transcript	c.1462G>A	p.Val488Met	missense_variant	11/19		XP_011515352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TONSL	ENST00000409379.8 linkuse as main transcript	c.1462G>A	p.Val488Met	missense_variant	11/26	1	NM_013432.5	ENSP00000386239.3		Q96HA7-1
TONSL	ENST00000497613.2 linkuse as main transcript	n.2437G>A		non_coding_transcript_exon_variant	3/17	2

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

2898

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0659

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00798

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.00489

AC:

1191

AN:

243416

Hom.:

AF XY:

0.00355

AC XY:

471

AN XY:

132862

show subpopulations

Gnomad AFR exome

AF:

0.0678

Gnomad AMR exome

AF:

0.00306

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000987

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000111

Gnomad OTH exome

AF:

0.00234

GnomAD4 exome

AF:

0.00188

AC:

2354

AN:

1251906

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

1005

AN XY:

633456

show subpopulations

Gnomad4 AFR exome

AF:

0.0671

Gnomad4 AMR exome

AF:

0.00322

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000171

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000336

Gnomad4 OTH exome

AF:

0.00359

GnomAD4 genome

AF:

0.0191

AC:

2909

AN:

152362

Hom.:

100

Cov.:

AF XY:

0.0188

AC XY:

1401

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0660

Gnomad4 AMR

AF:

0.00797

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.00578

Hom.:

Bravo

AF:

0.0218

ESP6500AA

AF:

0.0657

AC:

289

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00624

AC:

756

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

TONSL-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.6

DANN

Benign

0.97

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

MetaRNN

Benign

0.0027

Sift4G

Benign

0.85

Vest4

0.21

MVP

0.15

ClinPred

0.0037

GERP RS

-6.4

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

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