chr8-144429228-G-A

Variant names:

• chr8-144429228-G-A
• rs1823060639
• NM_013432.5:c.4052C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013432.5(TONSL):​c.4052C>T​(p.Ala1351Val) variant causes a missense 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1351G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TONSL NM_013432.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.462
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.101022094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5	c.4052C>T	p.Ala1351Val	missense_variant	Exon 26 of 26	ENST00000409379.8	NP_038460.4
TONSL	XM_011517048.3	c.3080C>T	p.Ala1027Val	missense_variant	Exon 19 of 19		XP_011515350.1
TONSL	XM_011517049.3	c.3044C>T	p.Ala1015Val	missense_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.4052C>T	p.Ala1351Val	missense_variant	Exon 26 of 26	1	NM_013432.5	ENSP00000386239.3
TONSL	ENST00000497613.2	n.6154C>T		non_coding_transcript_exon_variant	Exon 17 of 17	2
ENSG00000305609	ENST00000811933.1	n.199+1114G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.46
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.033
Sift	Benign	0.26	T
Sift4G	Benign	0.14	T
Polyphen		0.024	B
Vest4		0.17
MutPred		0.32		Loss of disorder (P = 0.0781);
MVP		0.061
MPC		0.25
ClinPred		0.17	T
GERP RS		-1.4
Varity_R		0.020
gMVP		0.42
Mutation Taster		=99/1	polymorphism

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: rs1823060639; hg19: chr8-145654611;