8-144443060-G-A

Variant names:

• chr8-144443060-G-A
• rs760477
• NM_013432.5:c.448+78C>T

Variant summary

Our verdict is Benign. The variant received -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
• 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 Gene-Disease associations (from GenCC):

• spondyloepimetaphyseal dysplasia, sponastrime type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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.

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.448+78C>T		intron	N/A	NP_038460.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TONSL	ENST00000409379.8	TSL:1 MANE Select	c.448+78C>T		intron	N/A	ENSP00000386239.3
	TONSL	ENST00000497613.2	TSL:2	n.-204C>T		upstream_gene	N/A

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

African (AFR) AF: 0.287 AC: 8584 AN: 29950

American (AMR) AF: 0.403 AC: 12726 AN: 31566

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 7207 AN: 21818

East Asian (EAS) AF: 0.345 AC: 12084 AN: 35074

South Asian (SAS) AF: 0.569 AC: 40469 AN: 71108

European-Finnish (FIN) AF: 0.519 AC: 23454 AN: 45162

Middle Eastern (MID) AF: 0.344 AC: 1860 AN: 5408

European-Non Finnish (NFE) AF: 0.472 AC: 484998 AN: 1026986

Other (OTH) AF: 0.443 AC: 24347 AN: 54974

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

African (AFR) AF: 0.293 AC: 12172 AN: 41522

American (AMR) AF: 0.403 AC: 6162 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1120 AN: 3468

East Asian (EAS) AF: 0.390 AC: 2019 AN: 5180

South Asian (SAS) AF: 0.582 AC: 2809 AN: 4830

European-Finnish (FIN) AF: 0.519 AC: 5503 AN: 10594

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.467 AC: 31711 AN: 67964

Other (OTH) AF: 0.416 AC: 880 AN: 2116

Alfa AF: 0.452 Hom.: 11112

Bravo AF: 0.397

Asia WGS AF: 0.492 AC: 1708 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.4
DANN	Benign	0.61
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs760477; hg19: chr8-145668443; COSMIC: COSV68049209; COSMIC: COSV68049209;