NM_013432.5:c.4086C>T

Variant names:

• chr8-144429194-G-A
• rs1554877934
• NM_013432.5:c.4086C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_013432.5(TONSL):​c.4086C>T​(p.Pro1362Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,382,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TONSL NM_013432.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.102
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 8-144429194-G-A is Benign according to our data. Variant chr8-144429194-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2874029.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.102 with no splicing effect.

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.4086C>T	p.Pro1362Pro	synonymous	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.4086C>T	p.Pro1362Pro	synonymous	Exon 26 of 26	ENSP00000386239.3	Q96HA7-1
	TONSL	ENST00000932056.1		c.4254C>T	p.Pro1418Pro	synonymous	Exon 27 of 27	ENSP00000602115.1
	TONSL	ENST00000971177.1		c.4116C>T	p.Pro1372Pro	synonymous	Exon 26 of 26	ENSP00000641236.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 134448 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1382132 Hom.: 0 Cov.: 30 AF XY: 0.00000293 AC XY: 2 AN XY: 681862

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31006

American (AMR) AF: 0.00 AC: 0 AN: 35426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25044

East Asian (EAS) AF: 0.00 AC: 0 AN: 35314

South Asian (SAS) AF: 0.00 AC: 0 AN: 78884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4642

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1076776

Other (OTH) AF: 0.00 AC: 0 AN: 57660

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.1
DANN	Benign	0.92
PhyloP100		-0.10

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: rs1554877934; hg19: chr8-145654577;