Genetic Variant NM_013432.5:c.3950C>G (chr8-144429330-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.3950C>G(p.Ala1317Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000775 in 1,290,714 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. A1317V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

TONSL
NM_013432.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.81

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=0.23346907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5 link	c.3950C>G	p.Ala1317Gly	missense_variant	Exon 26 of 26	ENST00000409379.8	NP_038460.4	Q96HA7-1
TONSL	XM_011517048.3 link	c.2978C>G	p.Ala993Gly	missense_variant	Exon 19 of 19		XP_011515350.1
TONSL	XM_011517049.3 link	c.2942C>G	p.Ala981Gly	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.3950C>G	p.Ala1317Gly	missense_variant	Exon 26 of 26	1	NM_013432.5	ENSP00000386239.3	Q96HA7-1
TONSL	ENST00000497613.2 link	n.6052C>G		non_coding_transcript_exon_variant	Exon 17 of 17	2
ENSG00000305609	ENST00000811933.1 link	n.199+1216G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000165

AC:

AN:

60464

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000933

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:

7.75e-7

AC:

AN:

1290714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

627570

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:

26390

American (AMR)

AF:

0.0000446

AC:

AN:

22406

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20254

East Asian (EAS)

AF:

0.00

AC:

AN:

31536

South Asian (SAS)

AF:

0.00

AC:

AN:

67176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3858

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1026848

Other (OTH)

AF:

0.00

AC:

AN:

53316

⚠️ 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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.12

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.27

M_CAP

Benign

0.031

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.27

PhyloP100

1.8

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.2

REVEL

Benign

0.10

Sift

Benign

0.36

Sift4G

Benign

0.22

Polyphen

0.0020

Vest4

0.15

MutPred

0.37

Gain of disorder (P = 0.1626);

MVP

0.29

MPC

0.14

ClinPred

0.091

GERP RS

5.4

Varity_R

0.14

gMVP

0.16

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

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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