chr8-144429228-G-C

Variant names:

• chr8-144429228-G-C
• rs1823060639
• NM_013432.5:c.4052C>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.4052C>G​(p.Ala1351Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,383,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TONSL NM_013432.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

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=0.14529142).

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.4052C>G	p.Ala1351Gly	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.4052C>G	p.Ala1351Gly	missense	Exon 26 of 26	ENSP00000386239.3	Q96HA7-1
	TONSL	ENST00000932056.1		c.4220C>G	p.Ala1407Gly	missense	Exon 27 of 27	ENSP00000602115.1
	TONSL	ENST00000971177.1		c.4082C>G	p.Ala1361Gly	missense	Exon 26 of 26	ENSP00000641236.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000137 AC: 19 AN: 1383690 Hom.: 0 Cov.: 31 AF XY: 0.0000103 AC XY: 7 AN XY: 682520

African (AFR) AF: 0.00 AC: 0 AN: 31180

American (AMR) AF: 0.00 AC: 0 AN: 35424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25086

East Asian (EAS) AF: 0.00 AC: 0 AN: 35438

South Asian (SAS) AF: 0.00 AC: 0 AN: 78924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4606

European-Non Finnish (NFE) AF: 0.0000176 AC: 19 AN: 1076854

Other (OTH) AF: 0.00 AC: 0 AN: 57648

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.46
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.066
Sift	Benign	0.055	T
Sift4G	Uncertain	0.015	D
Polyphen		0.28	B
Vest4		0.24
MutPred		0.33		Loss of stability (P = 0.1862)
MVP		0.12
MPC		0.30
ClinPred		0.15	T
GERP RS		-1.4
Varity_R		0.024
gMVP		0.26
Mutation Taster		=98/2	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;