8-144440133-T-C

Variant names:

• chr8-144440133-T-C
• rs2306383
• NM_013432.5:c.1368A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013432.5(TONSL):​c.1368A>G​(p.Leu456Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.981 in 1,612,168 control chromosomes in the GnomAD database, including 778,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L456L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.95 (69488 hom., cov: 34)
  • Exomes 𝑓: 0.98 (708634 hom.)
• Consequence: TONSL NM_013432.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.18
• Publications: 16 publications found

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-AS1 (HGNC:51556): (TONSL antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 8-144440133-T-C is Benign according to our data. Variant chr8-144440133-T-C is described in ClinVar as Benign. ClinVar VariationId is 1167023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TONSL	NM_013432.5	MANE Select	c.1368A>G	p.Leu456Leu	synonymous	Exon 11 of 26	NP_038460.4
	TONSL-AS1	NR_109770.1		n.*240T>C		downstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TONSL	ENST00000409379.8	TSL:1 MANE Select	c.1368A>G	p.Leu456Leu	synonymous	Exon 11 of 26	ENSP00000386239.3
	TONSL	ENST00000497613.2	TSL:2	n.2343A>G		non_coding_transcript_exon	Exon 3 of 17
	TONSL-AS1	ENST00000442850.1	TSL:5	n.*162T>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.954 AC: 145145 AN: 152188 Hom.: 69453 Cov.: 34

Gnomad AFR AF: 0.894

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.921

Gnomad ASJ AF: 0.987

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.996

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.964

GnomAD2 exomes AF: 0.958 AC: 236071 AN: 246478 AF XY: 0.966

Gnomad AFR exome AF: 0.892

Gnomad AMR exome AF: 0.881

Gnomad ASJ exome AF: 0.988

Gnomad EAS exome AF: 0.789

Gnomad FIN exome AF: 0.996

Gnomad NFE exome AF: 0.997

Gnomad OTH exome AF: 0.976

GnomAD4 exome AF: 0.984 AC: 1436730 AN: 1459862 Hom.: 708634 Cov.: 49 AF XY: 0.985 AC XY: 715670 AN XY: 726304

African (AFR) AF: 0.894 AC: 29888 AN: 33424

American (AMR) AF: 0.887 AC: 39395 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 25789 AN: 26106

East Asian (EAS) AF: 0.756 AC: 29988 AN: 39676

South Asian (SAS) AF: 0.997 AC: 86006 AN: 86222

European-Finnish (FIN) AF: 0.995 AC: 51936 AN: 52176

Middle Eastern (MID) AF: 0.991 AC: 5711 AN: 5764

European-Non Finnish (NFE) AF: 0.997 AC: 1108851 AN: 1111746

Other (OTH) AF: 0.980 AC: 59166 AN: 60348

GnomAD4 genome AF: 0.954 AC: 145232 AN: 152306 Hom.: 69488 Cov.: 34 AF XY: 0.952 AC XY: 70910 AN XY: 74480

African (AFR) AF: 0.894 AC: 37126 AN: 41548

American (AMR) AF: 0.920 AC: 14082 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.987 AC: 3428 AN: 3472

East Asian (EAS) AF: 0.799 AC: 4126 AN: 5164

South Asian (SAS) AF: 0.996 AC: 4810 AN: 4830

European-Finnish (FIN) AF: 0.997 AC: 10583 AN: 10620

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 67835 AN: 68044

Other (OTH) AF: 0.964 AC: 2040 AN: 2116

Alfa AF: 0.980 Hom.: 33162

Bravo AF: 0.944

Asia WGS AF: 0.932 AC: 3243 AN: 3478

EpiCase AF: 0.997

EpiControl AF: 0.997

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 13, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sponastrime dysplasia Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.5
DANN	Benign	0.42
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2306383; hg19: chr8-145665516; COSMIC: COSV68047637; COSMIC: COSV68047637;