rs760477

Positions:

• chr8-144443060-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013432.5(TONSL):​c.448+78C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 1,474,222 control chromosomes in the GnomAD database, including 159,132 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 0.41 (13582 hom., cov: 34)
  • Exomes 𝑓: 0.47 (145550 hom.)
• Consequence: TONSL NM_013432.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TONSL	NM_013432.5	c.448+78C>T		intron_variant		ENST00000409379.8	NP_038460.4
TONSL	XM_011517050.3	c.448+78C>T		intron_variant			XP_011515352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TONSL	ENST00000409379.8	c.448+78C>T		intron_variant		1	NM_013432.5	ENSP00000386239.3

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62928 AN: 152058 Hom.: 13589 Cov.: 34

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.416

GnomAD4 exome AF: 0.466 AC: 615729 AN: 1322046 Hom.: 145550 Cov.: 23 AF XY: 0.469 AC XY: 303211 AN XY: 646686

Gnomad4 AFR exome AF: 0.287

Gnomad4 AMR exome AF: 0.403

Gnomad4 ASJ exome AF: 0.330

Gnomad4 EAS exome AF: 0.345

Gnomad4 SAS exome AF: 0.569

Gnomad4 FIN exome AF: 0.519

Gnomad4 NFE exome AF: 0.472

Gnomad4 OTH exome AF: 0.443

GnomAD4 genome AF: 0.414 AC: 62939 AN: 152176 Hom.: 13582 Cov.: 34 AF XY: 0.416 AC XY: 30974 AN XY: 74404

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.390

Gnomad4 SAS AF: 0.582

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.467

Gnomad4 OTH AF: 0.416

Alfa AF: 0.461 Hom.: 7828

Bravo AF: 0.397

Asia WGS AF: 0.492 AC: 1708 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.4
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs760477; hg19: chr8-145668443; COSMIC: COSV68049209; COSMIC: COSV68049209;