Genetic Variant TONSL:c.1653+40T>C (chr8-144438431-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_013432.5(TONSL):c.1653+40T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,597,926 control chromosomes in the GnomAD database, including 217,353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 21418 hom., cov: 33)

Exomes 𝑓: 0.52 ( 195935 hom. )

Consequence

TONSL
NM_013432.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.26

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 8-144438431-A-G is Benign according to our data. Variant chr8-144438431-A-G is described in ClinVar as [Benign]. Clinvar id is 1342242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5 link	c.1653+40T>C		intron_variant	Intron 13 of 25	ENST00000409379.8	NP_038460.4	Q96HA7-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TONSL	ENST00000409379.8 link	c.1653+40T>C	intron_variant	Intron 13 of 25	1	NM_013432.5	ENSP00000386239.3	Q96HA7-1
TONSL-AS1	ENST00000442850.1 link	n.178+98A>G	intron_variant	Intron 2 of 3	5
TONSL	ENST00000497613.2 link	n.2628+40T>C	intron_variant	Intron 5 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.529

AC:

80368

AN:

151982

Hom.:

21409

Cov.:

show subpopulations

Gnomad AFR

AF:

0.558

Gnomad AMI

AF:

0.485

Gnomad AMR

AF:

0.509

Gnomad ASJ

AF:

0.631

Gnomad EAS

AF:

0.391

Gnomad SAS

AF:

0.408

Gnomad FIN

AF:

0.519

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.531

Gnomad OTH

AF:

0.523

GnomAD3 exomes

AF:

0.500

AC:

120407

AN:

240764

Hom.:

30531

AF XY:

0.500

AC XY:

65716

AN XY:

131302

show subpopulations

Gnomad AFR exome

AF:

0.549

Gnomad AMR exome

AF:

0.466

Gnomad ASJ exome

AF:

0.632

Gnomad EAS exome

AF:

0.373

Gnomad SAS exome

AF:

0.421

Gnomad FIN exome

AF:

0.518

Gnomad NFE exome

AF:

0.531

Gnomad OTH exome

AF:

0.527

GnomAD4 exome

AF:

0.518

AC:

749302

AN:

1445824

Hom.:

195935

Cov.:

AF XY:

0.516

AC XY:

370690

AN XY:

718632

show subpopulations

Gnomad4 AFR exome

AF:

0.560

Gnomad4 AMR exome

AF:

0.473

Gnomad4 ASJ exome

AF:

0.625

Gnomad4 EAS exome

AF:

0.396

Gnomad4 SAS exome

AF:

0.423

Gnomad4 FIN exome

AF:

0.516

Gnomad4 NFE exome

AF:

0.527

Gnomad4 OTH exome

AF:

0.533

GnomAD4 genome

AF:

0.529

AC:

80424

AN:

152102

Hom.:

21418

Cov.:

AF XY:

0.526

AC XY:

39137

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.557

Gnomad4 AMR

AF:

0.508

Gnomad4 ASJ

AF:

0.631

Gnomad4 EAS

AF:

0.390

Gnomad4 SAS

AF:

0.409

Gnomad4 FIN

AF:

0.519

Gnomad4 NFE

AF:

0.531

Gnomad4 OTH

AF:

0.523

Alfa

AF:

0.543

Hom.:

4251

Bravo

AF:

0.530

Asia WGS

AF:

0.426

AC:

1484

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sponastrime dysplasia

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.42

DANN

Benign

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over