rs863225135
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001134831.2(AHI1):āc.2687A>Gā(p.His896Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 1,610,562 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 Pathogenic (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.0000062 ( 0 hom. )
Consequence
AHI1
NM_001134831.2 missense
NM_001134831.2 missense
Scores
6
9
4
Clinical Significance
Conservation
PhyloP100: 7.40
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 Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894
PP5
Variant 6-135427244-T-C is Pathogenic according to our data. Variant chr6-135427244-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 217532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135427244-T-C is described in Lovd as [Pathogenic]. Variant chr6-135427244-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AHI1 | NM_001134831.2 | c.2687A>G | p.His896Arg | missense_variant | 20/29 | ENST00000265602.11 | NP_001128303.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AHI1 | ENST00000265602.11 | c.2687A>G | p.His896Arg | missense_variant | 20/29 | 1 | NM_001134831.2 | ENSP00000265602.6 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151638Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000617 AC: 9AN: 1458924Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 725698
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151638Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74082
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Joubert syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2017 | - - |
Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 15, 2023 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 896 of the AHI1 protein (p.His896Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Joubert syndrome or non-syndromic retinal dystrophy (PMID: 16155189, 28442542; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217532). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AHI1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
AHI1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 20, 2023 | The AHI1 c.2687A>G variant is predicted to result in the amino acid substitution p.His896Arg. This variant segregated with Joubert syndrome (JS) in a consanguineous family (affected siblings were homozygous for this variant and parents and the unaffected sibling were heterozygous) (Family K8134, Parisi et al. 2006. PubMed ID: 16155189). This variant in the homozygous state also been reported in a patient with non-syndromic retinitis pigmentosa and JS (Rosati et al. 2018. PubMed ID: 29334628). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
.;.;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;D
Vest4
MutPred
Gain of phosphorylation at S894 (P = 0.0961);Gain of phosphorylation at S894 (P = 0.0961);Gain of phosphorylation at S894 (P = 0.0961);Gain of phosphorylation at S894 (P = 0.0961);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at