rs4925856

Positions:

• chr8-144430520-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013432.5(TONSL):​c.3827C>T​(p.Pro1276Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,612,244 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0037 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (100 hom.)
• Consequence: TONSL NM_013432.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.74

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006611079).
• BP6: Variant 8-144430520-G-A is Benign according to our data. Variant chr8-144430520-G-A is described in ClinVar as [Benign]. Clinvar id is 1164724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TONSL	NM_013432.5	c.3827C>T	p.Pro1276Leu	missense_variant	25/26	ENST00000409379.8	NP_038460.4
TONSL	XM_011517048.3	c.2855C>T	p.Pro952Leu	missense_variant	18/19		XP_011515350.1
TONSL	XM_011517049.3	c.2819C>T	p.Pro940Leu	missense_variant	18/19		XP_011515351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TONSL	ENST00000409379.8	c.3827C>T	p.Pro1276Leu	missense_variant	25/26	1	NM_013432.5	ENSP00000386239.3
TONSL	ENST00000497613.2	n.5929C>T		non_coding_transcript_exon_variant	16/17	2

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 556 AN: 152242 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00952 AC: 2368 AN: 248778 Hom.: 85 AF XY: 0.00694 AC XY: 933 AN XY: 134506

Gnomad AFR exome AF: 0.000867

Gnomad AMR exome AF: 0.0680

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00661

GnomAD4 exome AF: 0.00202 AC: 2956 AN: 1459884 Hom.: 100 Cov.: 30 AF XY: 0.00165 AC XY: 1195 AN XY: 726218

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.0631

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00371 AC: 565 AN: 152360 Hom.: 12 Cov.: 33 AF XY: 0.00409 AC XY: 305 AN XY: 74504

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00191 Hom.: 21

Bravo AF: 0.00811

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00725 AC: 880

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000595

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

TONSL-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	0.16
Eigen_PC	Benign	0.092
FATHMM_MKL	Benign	0.75	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.047	D
Polyphen		0.91	P
Vest4		0.29
MVP		0.61
MPC		0.15
ClinPred		0.093	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs4925856; hg19: chr8-145655903;