rs4925857

Variant names:

• chr8-144434464-C-T
• rs4925857
• NM_013432.5:c.3086-185G>A

Variant summary

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

The NM_013432.5(TONSL):​c.3086-185G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 152,260 control chromosomes in the GnomAD database, including 139 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 0.015 (139 hom., cov: 34)
• Consequence: TONSL NM_013432.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175
• Publications: 3 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: Orphanet, G2P, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.184 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TONSL	NM_013432.5	MANE Select	c.3086-185G>A		intron	N/A	NP_038460.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TONSL	ENST00000409379.8	TSL:1 MANE Select	c.3086-185G>A		intron	N/A	ENSP00000386239.3	Q96HA7-1
	TONSL	ENST00000932056.1		c.3086-185G>A		intron	N/A	ENSP00000602115.1
	TONSL	ENST00000971177.1		c.3116-185G>A		intron	N/A	ENSP00000641236.1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2265 AN: 152144 Hom.: 137 Cov.: 34

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0654

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0144

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

GnomAD4 genome AF: 0.0149 AC: 2276 AN: 152260 Hom.: 139 Cov.: 34 AF XY: 0.0174 AC XY: 1296 AN XY: 74456

African (AFR) AF: 0.00274 AC: 114 AN: 41554

American (AMR) AF: 0.0660 AC: 1010 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.194 AC: 1004 AN: 5174

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4828

European-Finnish (FIN) AF: 0.00301 AC: 32 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 67992

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.00651 Hom.: 8

Bravo AF: 0.0206

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.88
PhyloP100		0.17
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: rs4925857; hg19: chr8-145659847;