Genetic Variant NM_013432.5:c.1368A>T (chr8-144440133-T-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_013432.5(TONSL):c.1368A>T(p.Leu456Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L456L) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TONSL
NM_013432.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.18

Publications

16 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 links:

TONSL-AS1 (HGNC:51556): (TONSL antisense RNA 1)

TONSL-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 8-144440133-T-A is Benign according to our data. Variant chr8-144440133-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2097714.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.18 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5 link	c.1368A>T	p.Leu456Leu	synonymous_variant	Exon 11 of 26	ENST00000409379.8	NP_038460.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TONSL	ENST00000409379.8 link	c.1368A>T	p.Leu456Leu	synonymous_variant	Exon 11 of 26	1	NM_013432.5	ENSP00000386239.3
TONSL	ENST00000497613.2 link	n.2343A>T		non_coding_transcript_exon_variant	Exon 3 of 17	2
TONSL-AS1	ENST00000442850.1 link	n.*162T>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000122

AC:

AN:

246478

AF XY:

0.0000224

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000411

AC:

AN:

1459914

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52176

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111746

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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.:

33162

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.7

(source)

DANN

Benign

0.62

PhyloP100

1.2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over