dbSNP rs2242264: TONSL:c.865+15G>C (chr8-144442022-C-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.865+15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.986 in 1,611,010 control chromosomes in the GnomAD database, including 784,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.98 ( 72830 hom., cov: 32)

Exomes 𝑓: 0.99 ( 711443 hom. )

Consequence

TONSL
NM_013432.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.79

Publications

6 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: Ambry Genetics, G2P, Orphanet, PanelApp Australia

TONSL 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=-1.01).

BP6

Variant 8-144442022-C-G is Benign according to our data. Variant chr8-144442022-C-G is described in ClinVar as Benign. ClinVar VariationId is 1167011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.991 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.865+15G>C		intron	N/A	NP_038460.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TONSL	ENST00000409379.8	TSL:1 MANE Select	c.865+15G>C	intron	N/A	ENSP00000386239.3	Q96HA7-1
TONSL	ENST00000932056.1		c.865+15G>C	intron	N/A	ENSP00000602115.1
TONSL	ENST00000971177.1		c.865+15G>C	intron	N/A	ENSP00000641236.1

Frequencies

GnomAD3 genomes

AF:

0.977

AC:

148688

AN:

152120

Hom.:

72786

Cov.:

show subpopulations

Gnomad AFR

AF:

0.976

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.929

Gnomad ASJ

AF:

0.989

Gnomad EAS

AF:

0.801

Gnomad SAS

AF:

0.997

Gnomad FIN

AF:

0.997

Gnomad MID

AF:

0.994

Gnomad NFE

AF:

0.997

Gnomad OTH

AF:

0.977

GnomAD2 exomes

AF:

0.965

AC:

239412

AN:

248224

AF XY:

0.971

show subpopulations

Gnomad AFR exome

AF:

0.976

Gnomad AMR exome

AF:

0.887

Gnomad ASJ exome

AF:

0.990

Gnomad EAS exome

AF:

0.789

Gnomad FIN exome

AF:

0.996

Gnomad NFE exome

AF:

0.997

Gnomad OTH exome

AF:

0.979

GnomAD4 exome

AF:

0.987

AC:

1439208

AN:

1458772

Hom.:

711443

Cov.:

AF XY:

0.987

AC XY:

716648

AN XY:

725734

show subpopulations

African (AFR)

AF:

0.978

AC:

32680

AN:

33432

American (AMR)

AF:

0.893

AC:

39897

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.989

AC:

25841

AN:

26120

East Asian (EAS)

AF:

0.756

AC:

29999

AN:

39682

South Asian (SAS)

AF:

0.998

AC:

85993

AN:

86192

European-Finnish (FIN)

AF:

0.995

AC:

51883

AN:

52122

Middle Eastern (MID)

AF:

0.995

AC:

5316

AN:

5342

European-Non Finnish (NFE)

AF:

0.998

AC:

1108210

AN:

1110950

Other (OTH)

AF:

0.986

AC:

59389

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

797

1594

2392

3189

3986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21622

43244

64866

86488

108110

<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:

0.977

AC:

148789

AN:

152238

Hom.:

72830

Cov.:

AF XY:

0.975

AC XY:

72566

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.976

AC:

40560

AN:

41552

American (AMR)

AF:

0.929

AC:

14199

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.989

AC:

3433

AN:

3472

East Asian (EAS)

AF:

0.800

AC:

4127

AN:

5156

South Asian (SAS)

AF:

0.997

AC:

4816

AN:

4830

European-Finnish (FIN)

AF:

0.997

AC:

10581

AN:

10618

Middle Eastern (MID)

AF:

0.993

AC:

292

AN:

294

European-Non Finnish (NFE)

AF:

0.997

AC:

67806

AN:

68000

Other (OTH)

AF:

0.977

AC:

2063

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

162

324

487

649

811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.989

Hom.:

13682

Bravo

AF:

0.971

Asia WGS

AF:

0.936

AC:

3257

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Sponastrime dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.97

(source)

DANN

Benign

0.33

PhyloP100

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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