8-144438493-C-T

Position:

chr8-144438493-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM2BP4_StrongBP6BS1

The NM_013432.5(TONSL):c.1631G>A(p.Arg544His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 1,613,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00065 ( 0 hom. )

Consequence

TONSL
NM_013432.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.23

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 (HGNC:):

TONSL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a repeat ANK 1 (size 29) in uniprot entity TONSL_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_013432.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052747875).

BP6

Variant 8-144438493-C-T is Benign according to our data. Variant chr8-144438493-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1593420.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00065 (950/1460678) while in subpopulation NFE AF= 0.000727 (808/1111918). AF 95% confidence interval is 0.000685. There are 0 homozygotes in gnomad4_exome. There are 434 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TONSL	NM_013432.5 linkuse as main transcript	c.1631G>A	p.Arg544His	missense_variant	13/26	ENST00000409379.8	NP_038460.4	Q96HA7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TONSL	ENST00000409379.8 linkuse as main transcript	c.1631G>A	p.Arg544His	missense_variant	13/26	1	NM_013432.5	ENSP00000386239.3	Q96HA7-1
TONSL	ENST00000497613.2 linkuse as main transcript	n.2606G>A		non_coding_transcript_exon_variant	5/17	2
TONSL-AS1	ENST00000442850.1 linkuse as main transcript	n.178+160C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000461

AC:

115

AN:

249514

Hom.:

AF XY:

0.000524

AC XY:

AN XY:

135444

show subpopulations

Gnomad AFR exome

AF:

0.000312

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00250

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000676

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000650

AC:

950

AN:

1460678

Hom.:

Cov.:

AF XY:

0.000597

AC XY:

434

AN XY:

726716

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00226

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000727

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.000302

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000689

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000470

AC:

EpiCase

AF:

0.00131

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.1631G>A (p.R544H) alteration is located in exon 13 (coding exon 13) of the TONSL gene. This alteration results from a G to A substitution at nucleotide position 1631, causing the arginine (R) at amino acid position 544 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.66

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.4

N;.

REVEL

Uncertain

0.30

Sift

Benign

0.097

T;.

Sift4G

Uncertain

0.020

D;T

Polyphen

1.0

D;.

Vest4

0.48

MVP

0.82

MPC

0.68

ClinPred

0.32

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.079

gMVP

0.31

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

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