chr8-144429228-G-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.4052C>G(p.Ala1351Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,383,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TONSL
NM_013432.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.462

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:

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=0.14529142).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5 link	c.4052C>G	p.Ala1351Gly	missense_variant	Exon 26 of 26	ENST00000409379.8	NP_038460.4	Q96HA7-1
TONSL	XM_011517048.3 link	c.3080C>G	p.Ala1027Gly	missense_variant	Exon 19 of 19		XP_011515350.1
TONSL	XM_011517049.3 link	c.3044C>G	p.Ala1015Gly	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.4052C>G	p.Ala1351Gly	missense_variant	Exon 26 of 26	1	NM_013432.5	ENSP00000386239.3	Q96HA7-1
TONSL	ENST00000497613.2 link	n.6154C>G		non_coding_transcript_exon_variant	Exon 17 of 17	2
ENSG00000305609	ENST00000811933.1 link	n.199+1114G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1383690

Hom.:

Cov.:

AF XY:

0.0000103

AC XY:

AN XY:

682520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31180

American (AMR)

AF:

0.00

AC:

AN:

35424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25086

East Asian (EAS)

AF:

0.00

AC:

AN:

35438

South Asian (SAS)

AF:

0.00

AC:

AN:

78924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4606

European-Non Finnish (NFE)

AF:

0.0000176

AC:

AN:

1076854

Other (OTH)

AF:

0.00

AC:

AN:

57648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 09, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4052C>G (p.A1351G) alteration is located in exon 26 (coding exon 26) of the TONSL gene. This alteration results from a C to G substitution at nucleotide position 4052, causing the alanine (A) at amino acid position 1351 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.21

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.15

M_CAP

Benign

0.052

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

0.46

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.3

REVEL

Benign

0.066

Sift

Benign

0.055

Sift4G

Uncertain

0.015

Polyphen

0.28

Vest4

0.24

MutPred

0.33

Loss of stability (P = 0.1862);

MVP

0.12

MPC

0.30

ClinPred

0.15

GERP RS

-1.4

Varity_R

0.024

gMVP

0.26

Mutation Taster

=98/2

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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chr8-144429228-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over