Genetic Variant TONSL:p.Arg1343Gly (chr8-144429253-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_013432.5(TONSL):c.4027C>G(p.Arg1343Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,377,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1343H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

TONSL
NM_013432.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0900

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

spondyloepimetaphyseal dysplasia, sponastrime type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics

TONSL links:

ENSG00000305609 (HGNC:):

ENSG00000305609 links:

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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=0.09882572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5 link	c.4027C>G	p.Arg1343Gly	missense_variant	Exon 26 of 26	ENST00000409379.8	NP_038460.4	Q96HA7-1
TONSL	XM_011517048.3 link	c.3055C>G	p.Arg1019Gly	missense_variant	Exon 19 of 19		XP_011515350.1
TONSL	XM_011517049.3 link	c.3019C>G	p.Arg1007Gly	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.4027C>G	p.Arg1343Gly	missense_variant	Exon 26 of 26	1	NM_013432.5	ENSP00000386239.3	Q96HA7-1
TONSL	ENST00000497613.2 link	n.6129C>G		non_coding_transcript_exon_variant	Exon 17 of 17	2
ENSG00000305609	ENST00000811933.1 link	n.199+1139G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000753

AC:

AN:

132782

AF XY:

0.0000139

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.26e-7

AC:

AN:

1377066

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

677928

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30744

American (AMR)

AF:

0.00

AC:

AN:

35040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24954

East Asian (EAS)

AF:

0.00

AC:

AN:

34970

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4502

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071370

Other (OTH)

AF:

0.00

AC:

AN:

57226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.7

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.16

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.090

M_CAP

Benign

0.023

MetaRNN

Benign

0.099

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

0.090

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.1

REVEL

Benign

0.042

Sift

Benign

0.36

Sift4G

Benign

0.53

Polyphen

0.30

Vest4

0.11

MutPred

0.42

Loss of stability (P = 0.0473);

MVP

0.22

MPC

0.17

ClinPred

0.075

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.076

gMVP

0.31

Mutation Taster

=93/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over