8-144429259-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013432.5(TONSL):c.4021A>G(p.Ser1341Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,523,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TONSL
NM_013432.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14

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:

ENSG00000305609 (HGNC:):

ENSG00000305609 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16389462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5 link	c.4021A>G	p.Ser1341Gly	missense_variant	Exon 26 of 26	ENST00000409379.8	NP_038460.4	Q96HA7-1
TONSL	XM_011517048.3 link	c.3049A>G	p.Ser1017Gly	missense_variant	Exon 19 of 19		XP_011515350.1
TONSL	XM_011517049.3 link	c.3013A>G	p.Ser1005Gly	missense_variant	Exon 19 of 19		XP_011515351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TONSL	ENST00000409379.8 link	c.4021A>G	p.Ser1341Gly	missense_variant	Exon 26 of 26	1	NM_013432.5	ENSP00000386239.3	Q96HA7-1
TONSL	ENST00000497613.2 link	n.6123A>G		non_coding_transcript_exon_variant	Exon 17 of 17	2
ENSG00000305609	ENST00000811933.1 link	n.199+1145T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000154

AC:

AN:

130180

AF XY:

0.0000141

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000126

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000255

GnomAD4 exome

AF:

0.00000219

AC:

AN:

1370958

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

674018

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30358

American (AMR)

AF:

0.00

AC:

AN:

34614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24850

East Asian (EAS)

AF:

0.00

AC:

AN:

34550

South Asian (SAS)

AF:

0.00

AC:

AN:

78336

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39888

Middle Eastern (MID)

AF:

0.000224

AC:

AN:

4466

European-Non Finnish (NFE)

AF:

9.37e-7

AC:

AN:

1067036

Other (OTH)

AF:

0.0000176

AC:

AN:

56860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000108

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TONSL-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1341 of the TONSL protein (p.Ser1341Gly). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

Eigen

Benign

0.016

Eigen_PC

Benign

0.039

FATHMM_MKL

Benign

0.67

M_CAP

Benign

0.066

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.3

PhyloP100

1.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

REVEL

Benign

0.070

Sift

Benign

0.27

Sift4G

Uncertain

0.0030

Polyphen

0.80

Vest4

0.16

MutPred

0.26

Loss of sheet (P = 0.0817);

MVP

0.65

MPC

0.32

ClinPred

0.90

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.12

gMVP

0.40

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over