dbSNP rs760477: TONSL:c.448+78C>T (chr8-144443060-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_013432.5(TONSL):c.448+78C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 1,474,222 control chromosomes in the GnomAD database, including 159,132 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.41 ( 13582 hom., cov: 34)

Exomes 𝑓: 0.47 ( 145550 hom. )

Consequence

TONSL
NM_013432.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.12

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 Gene-Disease associations (from GenCC):

spondyloepimetaphyseal dysplasia, sponastrime type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics

TONSL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5 link	c.448+78C>T		intron_variant	Intron 4 of 25	ENST00000409379.8	NP_038460.4
TONSL	XM_011517050.3 link	c.448+78C>T		intron_variant	Intron 4 of 18		XP_011515352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TONSL	ENST00000409379.8 link	c.448+78C>T		intron_variant	Intron 4 of 25	1	NM_013432.5	ENSP00000386239.3
TONSL	ENST00000497613.2 link	n.-204C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.414

AC:

62928

AN:

152058

Hom.:

13589

Cov.:

show subpopulations

Gnomad AFR

AF:

0.294

Gnomad AMI

AF:

0.513

Gnomad AMR

AF:

0.403

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.390

Gnomad SAS

AF:

0.582

Gnomad FIN

AF:

0.519

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.467

Gnomad OTH

AF:

0.416

GnomAD4 exome

AF:

0.466

AC:

615729

AN:

1322046

Hom.:

145550

Cov.:

AF XY:

0.469

AC XY:

303211

AN XY:

646686

show subpopulations

African (AFR)

AF:

0.287

AC:

8584

AN:

29950

American (AMR)

AF:

0.403

AC:

12726

AN:

31566

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

7207

AN:

21818

East Asian (EAS)

AF:

0.345

AC:

12084

AN:

35074

South Asian (SAS)

AF:

0.569

AC:

40469

AN:

71108

European-Finnish (FIN)

AF:

0.519

AC:

23454

AN:

45162

Middle Eastern (MID)

AF:

0.344

AC:

1860

AN:

5408

European-Non Finnish (NFE)

AF:

0.472

AC:

484998

AN:

1026986

Other (OTH)

AF:

0.443

AC:

24347

AN:

54974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

16567

33134

49701

66268

82835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14706

29412

44118

58824

73530

<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:

0.414

AC:

62939

AN:

152176

Hom.:

13582

Cov.:

AF XY:

0.416

AC XY:

30974

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.293

AC:

12172

AN:

41522

American (AMR)

AF:

0.403

AC:

6162

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1120

AN:

3468

East Asian (EAS)

AF:

0.390

AC:

2019

AN:

5180

South Asian (SAS)

AF:

0.582

AC:

2809

AN:

4830

European-Finnish (FIN)

AF:

0.519

AC:

5503

AN:

10594

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.467

AC:

31711

AN:

67964

Other (OTH)

AF:

0.416

AC:

880

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1909

3819

5728

7638

9547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<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:

0.452

Hom.:

11112

Bravo

AF:

0.397

Asia WGS

AF:

0.492

AC:

1708

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.4

(source)

DANN

Benign

0.61

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over