NM_013432.5:c.4119C>T

Variant names:

• chr8-144429161-G-A
• rs1823055649
• NM_013432.5:c.4119C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_013432.5(TONSL):​c.4119C>T​(p.Leu1373Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1373L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TONSL NM_013432.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5	c.4119C>T	p.Leu1373Leu	synonymous_variant	Exon 26 of 26	ENST00000409379.8	NP_038460.4
TONSL	XM_011517048.3	c.3147C>T	p.Leu1049Leu	synonymous_variant	Exon 19 of 19		XP_011515350.1
TONSL	XM_011517049.3	c.3111C>T	p.Leu1037Leu	synonymous_variant	Exon 19 of 19		XP_011515351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TONSL	ENST00000409379.8	c.4119C>T	p.Leu1373Leu	synonymous_variant	Exon 26 of 26	1	NM_013432.5	ENSP00000386239.3
TONSL	ENST00000497613.2	n.6221C>T		non_coding_transcript_exon_variant	Exon 17 of 17	2
ENSG00000305609	ENST00000811933.1	n.199+1047G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1378684 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 680214

African (AFR) AF: 0.00 AC: 0 AN: 30618

American (AMR) AF: 0.00 AC: 0 AN: 34776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24992

East Asian (EAS) AF: 0.00 AC: 0 AN: 35172

South Asian (SAS) AF: 0.00 AC: 0 AN: 78766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4608

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075914

Other (OTH) AF: 0.00 AC: 0 AN: 57546

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.91
PhyloP100		1.0

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: rs1823055649; hg19: chr8-145654544;