rs13312995

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001134831.2(AHI1):c.2488C>T(p.Arg830Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,524,050 control chromosomes in the GnomAD database, including 484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R830Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 40 hom., cov: 32)

Exomes 𝑓: 0.024 ( 444 hom. )

Consequence

AHI1
NM_001134831.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.29

Publications

29 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008873045).

BP6

Variant 6-135429886-G-A is Benign according to our data. Variant chr6-135429886-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0201 (3051/151600) while in subpopulation NFE AF = 0.0277 (1872/67678). AF 95% confidence interval is 0.0266. There are 40 homozygotes in GnomAd4. There are 1467 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2 link	c.2488C>T	p.Arg830Trp	missense_variant	Exon 18 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.2488C>T	p.Arg830Trp	missense_variant	Exon 18 of 29	1	NM_001134831.2	ENSP00000265602.6		Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.0201

AC:

3049

AN:

151484

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00610

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0251

Gnomad ASJ

AF:

0.0359

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00810

Gnomad FIN

AF:

0.0250

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0276

Gnomad OTH

AF:

0.0236

GnomAD2 exomes

AF:

0.0201

AC:

4173

AN:

207212

AF XY:

0.0204

show subpopulations

Gnomad AFR exome

AF:

0.00599

Gnomad AMR exome

AF:

0.0177

Gnomad ASJ exome

AF:

0.0360

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0240

Gnomad NFE exome

AF:

0.0265

Gnomad OTH exome

AF:

0.0257

GnomAD4 exome

AF:

0.0242

AC:

33229

AN:

1372450

Hom.:

444

Cov.:

AF XY:

0.0240

AC XY:

16341

AN XY:

682210

show subpopulations

African (AFR)

AF:

0.00475

AC:

151

AN:

31816

American (AMR)

AF:

0.0185

AC:

750

AN:

40502

Ashkenazi Jewish (ASJ)

AF:

0.0371

AC:

932

AN:

25094

East Asian (EAS)

AF:

0.0000259

AC:

AN:

38634

South Asian (SAS)

AF:

0.0104

AC:

820

AN:

78566

European-Finnish (FIN)

AF:

0.0236

AC:

1204

AN:

51038

Middle Eastern (MID)

AF:

0.0355

AC:

198

AN:

5584

European-Non Finnish (NFE)

AF:

0.0267

AC:

27828

AN:

1043824

Other (OTH)

AF:

0.0234

AC:

1345

AN:

57392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1287

2574

3862

5149

6436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1020

2040

3060

4080

5100

<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

AF:

0.0201

AC:

3051

AN:

151600

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1467

AN XY:

74086

show subpopulations

African (AFR)

AF:

0.00611

AC:

253

AN:

41418

American (AMR)

AF:

0.0251

AC:

382

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.0359

AC:

124

AN:

3456

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00811

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0250

AC:

263

AN:

10534

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0277

AC:

1872

AN:

67678

Other (OTH)

AF:

0.0233

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

151

301

452

602

753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0251

Hom.:

189

Bravo

AF:

0.0198

TwinsUK

AF:

0.0262

AC:

ALSPAC

AF:

0.0301

AC:

116

ESP6500AA

AF:

0.00608

AC:

ESP6500EA

AF:

0.0263

AC:

214

ExAC

AF:

0.0178

AC:

2135

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 02, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Apr 02, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joubert syndrome 3

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Joubert syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Joubert syndrome 1

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

D;D;D;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.97

.;.;D;D

MetaRNN

Benign

0.0089

T;T;T;T

MetaSVM

Uncertain

-0.082

MutationAssessor

Pathogenic

3.3

M;M;M;M

PhyloP100

2.3

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.7

D;D;D;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.33

MPC

0.30

ClinPred

0.033

GERP RS

4.0

Varity_R

0.58

gMVP

0.75

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over