chr8-144438511-ATGCAGGCTCGG-A

Variant names:

• chr8-144438511-ATGCAGGCTCGG-A
• rs1586692058
• NM_013432.5:c.1602_1612delCCGAGCCTGCA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_013432.5(TONSL):​c.1602_1612delCCGAGCCTGCA​(p.Ala536GlyfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TONSL NM_013432.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.66

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-AS1 (HGNC:51556): (TONSL antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-144438511-ATGCAGGCTCGG-A is Pathogenic according to our data. Variant chr8-144438511-ATGCAGGCTCGG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 638063.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-144438511-ATGCAGGCTCGG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TONSL	NM_013432.5	c.1602_1612delCCGAGCCTGCA	p.Ala536GlyfsTer17	frameshift_variant	Exon 13 of 26	ENST00000409379.8	NP_038460.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TONSL	ENST00000409379.8	c.1602_1612delCCGAGCCTGCA	p.Ala536GlyfsTer17	frameshift_variant	Exon 13 of 26	1	NM_013432.5	ENSP00000386239.3
TONSL	ENST00000497613.2	n.2577_2587delCCGAGCCTGCA		non_coding_transcript_exon_variant	Exon 5 of 17	2
TONSL-AS1	ENST00000442850.1	n.179-160_179-150delGCTCGGTGCAG		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Sponastrime dysplasia Pathogenic:2

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 24, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1586692058; hg19: chr8-145663894;