NM_001134831.2:c.2012C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_001134831.2(AHI1):​c.2012C>T​(p.Thr671Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000407 in 1,424,334 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T671A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

AHI1
NM_001134831.2 missense

Scores

10
7
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 8.88

Publications

3 publications found
Variant links:
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]
AHI1 Gene-Disease associations (from GenCC):
  • Joubert syndrome 3
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
  • Joubert syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Joubert syndrome with ocular defect
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • retinitis pigmentosa
    Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001134831.2
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
Variant 6-135438399-G-A is Pathogenic according to our data. Variant chr6-135438399-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AHI1NM_001134831.2 linkc.2012C>T p.Thr671Ile missense_variant Exon 15 of 29 ENST00000265602.11 NP_001128303.1 Q8N157-1Q8NER0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AHI1ENST00000265602.11 linkc.2012C>T p.Thr671Ile missense_variant Exon 15 of 29 1 NM_001134831.2 ENSP00000265602.6 Q8N157-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000407
AC:
58
AN:
1424334
Hom.:
0
Cov.:
30
AF XY:
0.0000369
AC XY:
26
AN XY:
704898
show subpopulations
African (AFR)
AF:
0.0000304
AC:
1
AN:
32874
American (AMR)
AF:
0.00
AC:
0
AN:
40790
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25288
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38488
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79982
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51318
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5688
European-Non Finnish (NFE)
AF:
0.0000522
AC:
57
AN:
1090982
Other (OTH)
AF:
0.00
AC:
0
AN:
58924
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.487
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Joubert syndrome 3 Pathogenic:1
Feb 23, 2015
UW Hindbrain Malformation Research Program, University of Washington
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

Joubert syndrome Pathogenic:1
Dec 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 671 of the AHI1 protein (p.Thr671Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 16155189). ClinVar contains an entry for this variant (Variation ID: 217528). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

not provided Pathogenic:1
Apr 03, 2024
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28442542, 26003401, 31589614, 26092869, 15467982, 16155189) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.36
T;T;T;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
.;.;D;D
M_CAP
Uncertain
0.096
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Uncertain
0.18
D
MutationAssessor
Pathogenic
3.0
M;M;M;M
PhyloP100
8.9
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-3.3
D;D;D;D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.95
MutPred
0.89
Loss of disorder (P = 0.0281);Loss of disorder (P = 0.0281);Loss of disorder (P = 0.0281);Loss of disorder (P = 0.0281);
MVP
0.90
MPC
0.30
ClinPred
0.99
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.80
gMVP
0.75
Mutation Taster
=4/96
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs772989270; hg19: chr6-135759537; API