rs4082353

Variant names:

• chr8-144430189-T-G
• rs4082353
• NM_013432.5:c.3943+215A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013432.5(TONSL):​c.3943+215A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 152,056 control chromosomes in the GnomAD database, including 23,506 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 0.55 (23506 hom., cov: 33)
• Consequence: TONSL NM_013432.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00600
• Publications: 6 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

ENSG00000305609 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5	c.3943+215A>C		intron_variant	Intron 25 of 25	ENST00000409379.8	NP_038460.4
TONSL	XM_011517048.3	c.2971+215A>C		intron_variant	Intron 18 of 18		XP_011515350.1
TONSL	XM_011517049.3	c.2935+215A>C		intron_variant	Intron 18 of 18		XP_011515351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TONSL	ENST00000409379.8	c.3943+215A>C		intron_variant	Intron 25 of 25	1	NM_013432.5	ENSP00000386239.3
TONSL	ENST00000497613.2	n.6045+215A>C		intron_variant	Intron 16 of 16	2
ENSG00000305609	ENST00000811933.1	n.199+2075T>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84123 AN: 151938 Hom.: 23479 Cov.: 33

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.544

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.554 AC: 84212 AN: 152056 Hom.: 23506 Cov.: 33 AF XY: 0.554 AC XY: 41161 AN XY: 74304

African (AFR) AF: 0.593 AC: 24573 AN: 41468

American (AMR) AF: 0.576 AC: 8800 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2384 AN: 3470

East Asian (EAS) AF: 0.587 AC: 3025 AN: 5156

South Asian (SAS) AF: 0.410 AC: 1976 AN: 4824

European-Finnish (FIN) AF: 0.524 AC: 5541 AN: 10578

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.532 AC: 36136 AN: 67962

Other (OTH) AF: 0.545 AC: 1148 AN: 2108

Alfa AF: 0.549 Hom.: 3415

Bravo AF: 0.562

Asia WGS AF: 0.489 AC: 1703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.67
PhyloP100		-0.0060
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: rs4082353; hg19: chr8-145655572; COSMIC: COSV52873675; COSMIC: COSV52873675;