8-144442709-G-C

Variant names:

• chr8-144442709-G-C
• rs35913924
• NM_013432.5:c.546C>G

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.546C>G​(p.Asn182Lys) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N182N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TONSL NM_013432.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900
• Publications: 4 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: 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=0.11541626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5	c.546C>G	p.Asn182Lys	missense_variant	Exon 5 of 26	ENST00000409379.8	NP_038460.4
TONSL	XM_011517050.3	c.546C>G	p.Asn182Lys	missense_variant	Exon 5 of 19		XP_011515352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TONSL	ENST00000409379.8	c.546C>G	p.Asn182Lys	missense_variant	Exon 5 of 26	1	NM_013432.5	ENSP00000386239.3
TONSL	ENST00000497613.2	n.148C>G		non_coding_transcript_exon_variant	Exon 1 of 17	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250722 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.2
DANN	Benign	0.88
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		-0.0090
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N;.
REVEL	Benign	0.28
Sift	Benign	0.32	T;.
Sift4G	Benign	0.34	T;D
Polyphen		0.91	P;.
Vest4		0.28
MutPred		0.49		Gain of methylation at N182 (P = 0.0235);.;
MVP		0.21
MPC		0.25
ClinPred		0.43	T
GERP RS		-6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.13
Mutation Taster		=90/10	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: rs35913924; hg19: chr8-145668092;