chr8-144429199-C-A

Variant names:

• chr8-144429199-C-A
• rs112909141
• NM_013432.5:c.4081G>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.4081G>T​(p.Gly1361Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,382,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1361V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TONSL NM_013432.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.285
• 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]

VPS28 (HGNC:18178): (VPS28 subunit of ESCRT-I) This gene encodes a protein subunit of the ESCRT-I complex (endosomal complexes required for transport), which functions in the transport and sorting of proteins into subcellular vesicles. This complex can also be hijacked to facilitate the budding of enveloped viruses from the cell membrane. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

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=0.08471352).

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.4081G>T	p.Gly1361Cys	missense	Exon 26 of 26	NP_038460.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TONSL	ENST00000409379.8	TSL:1 MANE Select	c.4081G>T	p.Gly1361Cys	missense	Exon 26 of 26	ENSP00000386239.3	Q96HA7-1
	TONSL	ENST00000932056.1		c.4249G>T	p.Gly1417Cys	missense	Exon 27 of 27	ENSP00000602115.1
	TONSL	ENST00000971177.1		c.4111G>T	p.Gly1371Cys	missense	Exon 26 of 26	ENSP00000641236.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1382534 Hom.: 0 Cov.: 30 AF XY: 0.00000293 AC XY: 2 AN XY: 682090

African (AFR) AF: 0.00 AC: 0 AN: 31034

American (AMR) AF: 0.00 AC: 0 AN: 35466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25052

East Asian (EAS) AF: 0.00 AC: 0 AN: 35326

South Asian (SAS) AF: 0.00 AC: 0 AN: 78926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4640

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1076908

Other (OTH) AF: 0.00 AC: 0 AN: 57654

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.68
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.18	N
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.28
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.058
Sift	Benign	0.18	T
Sift4G	Benign	0.12	T
Polyphen		0.0030	B
Vest4		0.19
MutPred		0.18		Gain of catalytic residue at P1360 (P = 0.0279)
MVP		0.12
MPC		0.15
ClinPred		0.074	T
GERP RS		1.8
Varity_R		0.073
gMVP		0.39
Mutation Taster		=96/4	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: rs112909141; hg19: chr8-145654582;