14-20295764-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138376.3(TTC5):c.787C>T(p.Arg263*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_138376.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTC5 | ENST00000258821.8 | c.787C>T | p.Arg263* | stop_gained | 7/10 | 1 | NM_138376.3 | ENSP00000258821.3 | ||
TTC5 | ENST00000383029.7 | n.*332C>T | non_coding_transcript_exon_variant | 7/10 | 1 | ENSP00000372496.3 | ||||
TTC5 | ENST00000383029.7 | n.*332C>T | 3_prime_UTR_variant | 7/10 | 1 | ENSP00000372496.3 | ||||
TTC5 | ENST00000554157.5 | n.798C>T | non_coding_transcript_exon_variant | 7/9 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251092Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135842
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461756Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 727204
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Homozygote nonsense variant c.787C>T in Exon 7 of the TTC5 gene that results in the amino acid substitution p.Arg263* was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variation ID: 1048623). The variant has been previously reported by Rasheed A, et al., 2020 for developmental delay and intellectual disabilities. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop-gained variant c.787C>T (p.Arg263Ter) in the TTC5 gene has been reported in the homozygous state in an individual affected with delayed developmental milestones and intellectual disability (Rasheed et al., 2021). This variant is reported with the allele frequency (0.0007%) in the gnomAD Exomes and absent in 1000 Genomes. It has been submitted to ClinVar as Pathogenic. However, study on multiple affected individuals and functional studies on the pathogenicity of the variant is unavailable. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at