8-144440024-C-T

Position:

• chr8-144440024-C-T

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.1477G>A​(p.Gly493Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,224,910 control chromosomes in the GnomAD database, including 167,745 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.54 (22161 hom., cov: 34)
  • Exomes 𝑓: 0.52 (145584 hom.)
• Consequence: TONSL NM_013432.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.812

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.515272E-6).
• BP6: Variant 8-144440024-C-T is Benign according to our data. Variant chr8-144440024-C-T is described in ClinVar as [Benign]. Clinvar id is 1167022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TONSL	NM_013432.5	c.1477G>A	p.Gly493Ser	missense_variant	11/26	ENST00000409379.8	NP_038460.4
TONSL	XM_011517048.3	c.505G>A	p.Gly169Ser	missense_variant	4/19		XP_011515350.1
TONSL	XM_011517049.3	c.469G>A	p.Gly157Ser	missense_variant	4/19		XP_011515351.1
TONSL	XM_011517050.3	c.1477G>A	p.Gly493Ser	missense_variant	11/19		XP_011515352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TONSL	ENST00000409379.8	c.1477G>A	p.Gly493Ser	missense_variant	11/26	1	NM_013432.5	ENSP00000386239.3
TONSL	ENST00000497613.2	n.2452G>A		non_coding_transcript_exon_variant	3/17	2

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81685 AN: 152012 Hom.: 22144 Cov.: 34

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.529

GnomAD3 exomes AF: 0.503 AC: 121897 AN: 242106 Hom.: 31222 AF XY: 0.503 AC XY: 66432 AN XY: 132120

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.465

Gnomad ASJ exome AF: 0.665

Gnomad EAS exome AF: 0.371

Gnomad SAS exome AF: 0.423

Gnomad FIN exome AF: 0.517

Gnomad NFE exome AF: 0.530

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.517 AC: 554447 AN: 1072780 Hom.: 145584 Cov.: 15 AF XY: 0.514 AC XY: 283214 AN XY: 550800

Gnomad4 AFR exome AF: 0.589

Gnomad4 AMR exome AF: 0.472

Gnomad4 ASJ exome AF: 0.661

Gnomad4 EAS exome AF: 0.395

Gnomad4 SAS exome AF: 0.424

Gnomad4 FIN exome AF: 0.516

Gnomad4 NFE exome AF: 0.526

Gnomad4 OTH exome AF: 0.534

GnomAD4 genome AF: 0.537 AC: 81752 AN: 152130 Hom.: 22161 Cov.: 34 AF XY: 0.535 AC XY: 39770 AN XY: 74358

Gnomad4 AFR AF: 0.587

Gnomad4 AMR AF: 0.508

Gnomad4 ASJ AF: 0.667

Gnomad4 EAS AF: 0.390

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.520

Gnomad4 NFE AF: 0.530

Gnomad4 OTH AF: 0.529

Alfa AF: 0.533 Hom.: 25346

Bravo AF: 0.540

TwinsUK AF: 0.517 AC: 1918

ALSPAC AF: 0.511 AC: 1968

ESP6500AA AF: 0.578 AC: 2541

ESP6500EA AF: 0.535 AC: 4593

ExAC AF: 0.502 AC: 60677

Asia WGS AF: 0.423 AC: 1474 AN: 3478

EpiCase AF: 0.534

EpiControl AF: 0.536

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Sponastrime dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.74
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0000095	T
Sift4G	Benign	0.31	T
Vest4		0.032
ClinPred		0.0033	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs2229315; hg19: chr8-145665407; COSMIC: COSV68048177; COSMIC: COSV68048177;