rs1276908141
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate
The NM_001134831.2(AHI1):c.2106G>A(p.Thr702=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,684 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 Pathogenic (★).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
AHI1
NM_001134831.2 synonymous
NM_001134831.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.602
Genes affected
AHI1 (HGNC:21575): (Abelson helper integration site 1) This gene is apparently required for both cerebellar and cortical development in humans. This gene mutations cause specific forms of Joubert syndrome-related disorders. Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 6-135433187-C-T is Pathogenic according to our data. Variant chr6-135433187-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 461743.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-135433187-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AHI1 | NM_001134831.2 | c.2106G>A | p.Thr702= | synonymous_variant | 16/29 | ENST00000265602.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AHI1 | ENST00000265602.11 | c.2106G>A | p.Thr702= | synonymous_variant | 16/29 | 1 | NM_001134831.2 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 152060Hom.: 0 Cov.: 32 FAILED QC
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248768Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134946
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GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460684Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726698
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GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152060Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74266
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 13, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 461743). This variant has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 34205586; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects codon 702 of the AHI1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the AHI1 protein. - |
Computational scores
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BayesDel_noAF
Benign
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at