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

Variant summary

Our verdict is Benign. The variant received -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

Publications

9 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: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013432.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TONSL	NM_013432.5	MANE Select	c.1653+40T>C		intron	N/A	NP_038460.4
	TONSL-AS1	NR_109770.1		n.672+98A>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TONSL	ENST00000409379.8	TSL:1 MANE Select	c.1653+40T>C	intron	N/A	ENSP00000386239.3	Q96HA7-1
TONSL	ENST00000932056.1		c.1653+40T>C	intron	N/A	ENSP00000602115.1
TONSL	ENST00000971177.1		c.1653+40T>C	intron	N/A	ENSP00000641236.1

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

GnomAD2 exomes

AF:

0.500

AC:

120407

AN:

240764

AF XY:

0.500

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 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

African (AFR)

AF:

0.560

AC:

18624

AN:

33280

American (AMR)

AF:

0.473

AC:

20976

AN:

44364

Ashkenazi Jewish (ASJ)

AF:

0.625

AC:

16216

AN:

25938

East Asian (EAS)

AF:

0.396

AC:

15595

AN:

39394

South Asian (SAS)

AF:

0.423

AC:

36280

AN:

85858

European-Finnish (FIN)

AF:

0.516

AC:

25168

AN:

48770

Middle Eastern (MID)

AF:

0.640

AC:

3494

AN:

5462

European-Non Finnish (NFE)

AF:

0.527

AC:

581076

AN:

1102938

Other (OTH)

AF:

0.533

AC:

31873

AN:

59820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

19422

38844

58267

77689

97111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16590

33180

49770

66360

82950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.529

AC:

80424

AN:

152102

Hom.:

21418

Cov.:

AF XY:

0.526

AC XY:

39137

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.557

AC:

23128

AN:

41490

American (AMR)

AF:

0.508

AC:

7762

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.631

AC:

2190

AN:

3472

East Asian (EAS)

AF:

0.390

AC:

2021

AN:

5178

South Asian (SAS)

AF:

0.409

AC:

1973

AN:

4826

European-Finnish (FIN)

AF:

0.519

AC:

5493

AN:

10576

Middle Eastern (MID)

AF:

0.643

AC:

189

AN:

294

European-Non Finnish (NFE)

AF:

0.531

AC:

36123

AN:

67966

Other (OTH)

AF:

0.523

AC:

1104

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1964

3929

5893

7858

9822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

710

1420

2130

2840

3550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.543

Hom.:

4251

Bravo

AF:

0.530

Asia WGS

AF:

0.426

AC:

1484

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Sponastrime dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.42

(source)

DANN

Benign

0.36

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over