rs974371363

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001134831.2(AHI1):​c.1915T>C​(p.Tyr639His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

AHI1
NM_001134831.2 missense, splice_region

Scores

11
7
1

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 8.27
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AHI1NM_001134831.2 linkc.1915T>C p.Tyr639His missense_variant, splice_region_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.1915T>C p.Tyr639His missense_variant, splice_region_variant Exon 15 of 29 1 NM_001134831.2 ENSP00000265602.6 Q8N157-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

not provided Uncertain:1
Sep 16, 2018
Gharavi Laboratory, Columbia University
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D;D;D;.
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
.;.;D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.93
D;D;D;D
MetaSVM
Uncertain
0.24
D
MutationAssessor
Uncertain
2.2
M;M;M;M
PrimateAI
Pathogenic
0.80
D
PROVEAN
Uncertain
-4.3
D;D;D;D
REVEL
Pathogenic
0.80
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.93
MutPred
0.76
Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);
MVP
0.81
MPC
0.33
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.76
gMVP
0.76

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs974371363; hg19: chr6-135759634; API