14-44962496-CA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_001308120.2(TOGARAM1):​c.76delA​(p.Ser26ValfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TOGARAM1
NM_001308120.2 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.250
Variant links:
Genes affected
TOGARAM1 (HGNC:19959): (TOG array regulator of axonemal microtubules 1) Predicted to enable microtubule binding activity. Predicted to be involved in organelle assembly and positive regulation of microtubule polymerization. Predicted to be located in ciliary basal body. Predicted to be active in cilium and microtubule cytoskeleton. Predicted to colocalize with microtubule. Implicated in Joubert syndrome. [provided by Alliance of Genome Resources, Apr 2022]
KLHL28 (HGNC:19741): (kelch like family member 28)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-44962496-CA-C is Pathogenic according to our data. Variant chr14-44962496-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3393417.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TOGARAM1NM_001308120.2 linkc.76delA p.Ser26ValfsTer17 frameshift_variant Exon 1 of 20 ENST00000361462.7 NP_001295049.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TOGARAM1ENST00000361462.7 linkc.76delA p.Ser26ValfsTer17 frameshift_variant Exon 1 of 20 1 NM_001308120.2 ENSP00000354917.2 G3XAE9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Joubert syndrome 37 Pathogenic:1
Jul 22, 2023
Neuberg Centre For Genomic Medicine, NCGM
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The observed frameshift c.76delp.Ser26ValfsTer17 variant in TOGARAM1 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Ser26ValfsTer17 variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. This variant causes a frameshift starting with codon Serine 26, changes this amino acid to Valine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Ser26ValfsTer17. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-45431699; API