dbSNP rs741970: TONSL:c.265-160G>A (chr8-144443481-C-T) – 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.265-160G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 695,290 control chromosomes in the GnomAD database, including 962 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 0.021 ( 245 hom., cov: 33)

Exomes 𝑓: 0.018 ( 717 hom. )

Consequence

TONSL
NM_013432.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.408

Publications

1 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=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5 link	c.265-160G>A		intron_variant	Intron 3 of 25	ENST00000409379.8	NP_038460.4	Q96HA7-1
TONSL	XM_011517050.3 link	c.265-160G>A		intron_variant	Intron 3 of 18		XP_011515352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TONSL	ENST00000409379.8 link	c.265-160G>A		intron_variant	Intron 3 of 25	1	NM_013432.5	ENSP00000386239.3		Q96HA7-1

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3270

AN:

152230

Hom.:

246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.163

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.00583

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00229

Gnomad OTH

AF:

0.0220

GnomAD4 exome

AF:

0.0182

AC:

9889

AN:

542942

Hom.:

717

AF XY:

0.0173

AC XY:

4848

AN XY:

280856

show subpopulations

African (AFR)

AF:

0.00318

AC:

AN:

14144

American (AMR)

AF:

0.168

AC:

3206

AN:

19118

Ashkenazi Jewish (ASJ)

AF:

0.000562

AC:

AN:

14234

East Asian (EAS)

AF:

0.155

AC:

4885

AN:

31416

South Asian (SAS)

AF:

0.00960

AC:

455

AN:

47410

European-Finnish (FIN)

AF:

0.00450

AC:

133

AN:

29570

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

2158

European-Non Finnish (NFE)

AF:

0.00172

AC:

612

AN:

355806

Other (OTH)

AF:

0.0185

AC:

539

AN:

29086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

435

871

1306

1742

2177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.0214

AC:

3267

AN:

152348

Hom.:

245

Cov.:

AF XY:

0.0249

AC XY:

1858

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00293

AC:

122

AN:

41590

American (AMR)

AF:

0.128

AC:

1958

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.163

AC:

844

AN:

5176

South Asian (SAS)

AF:

0.0155

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00583

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00229

AC:

156

AN:

68036

Other (OTH)

AF:

0.0213

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

143

286

428

571

714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00847

Hom.:

Bravo

AF:

0.0311

Asia WGS

AF:

0.0770

AC:

266

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.8

(source)

DANN

Benign

0.75

PhyloP100

-0.41

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