6-135431282-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_001134831.2(AHI1):c.2299G>T(p.Val767Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000311 in 1,607,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

AHI1
NM_001134831.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.307

Publications

1 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

AHI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001134831.2

BP4

Computational evidence support a benign effect (MetaRNN=0.03901565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2 link	c.2299G>T	p.Val767Leu	missense_variant	Exon 17 of 29	ENST00000265602.11	NP_001128303.1	Q8N157-1Q8NER0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11 link	c.2299G>T	p.Val767Leu	missense_variant	Exon 17 of 29	1	NM_001134831.2	ENSP00000265602.6		Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000370

AC:

AN:

242950

AF XY:

0.0000304

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000547

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000337

AC:

AN:

1455988

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

724000

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33372

American (AMR)

AF:

0.00

AC:

AN:

44380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39454

South Asian (SAS)

AF:

0.0000586

AC:

AN:

85358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53172

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000316

AC:

AN:

1108414

Other (OTH)

AF:

0.0000333

AC:

AN:

60106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74218

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000242

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67922

Other (OTH)

AF:

0.00

AC:

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Joubert syndrome

Uncertain:1

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 767 of the AHI1 protein (p.Val767Leu). This variant is present in population databases (rs755688765, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 30755392). ClinVar contains an entry for this variant (Variation ID: 260843). 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 not expected to disrupt AHI1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Joubert syndrome 3

Uncertain:1

Apr 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.46

CADD

Benign

9.0

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.076

T;T;T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.099

LIST_S2

Uncertain

0.86

.;.;D;D

M_CAP

Benign

0.0064

MetaRNN

Benign

0.039

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.41

N;N;N;N

PhyloP100

0.31

PrimateAI

Benign

0.37

PROVEAN

Benign

0.47

N;N;N;N

REVEL

Benign

0.060

Sift

Benign

0.72

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.13

B;B;B;B

Vest4

0.14

MutPred

0.57

Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);

MVP

0.26

MPC

0.044

ClinPred

0.041

GERP RS

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.074

gMVP

0.26

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

6-135431282-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over