rs41288015

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.2624-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,605,156 control chromosomes in the GnomAD database, including 443 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 37 hom., cov: 32)

Exomes 𝑓: 0.021 ( 406 hom. )

Consequence

AHI1
NM_001134831.2 splice_region, intron

Scores

Splicing: ADA: 0.0002084

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.540

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

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 (BayesDel_noAF=-0.65).

BP6

Variant 6-135427313-T-C is Benign according to our data. Variant chr6-135427313-T-C is described in ClinVar as [Benign]. Clinvar id is 128325.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 = 0.0158 (2392/151688) while in subpopulation NFE AF = 0.0246 (1663/67582). AF 95% confidence interval is 0.0236. There are 37 homozygotes in GnomAd4. There are 1150 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 37 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2 link	c.2624-6A>G		splice_region_variant, intron_variant	Intron 19 of 28	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.2624-6A>G		splice_region_variant, intron_variant	Intron 19 of 28	1	NM_001134831.2	ENSP00000265602.6		Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2393

AN:

151570

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00457

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0116

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0270

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0156

AC:

3740

AN:

239992

AF XY:

0.0151

show subpopulations

Gnomad AFR exome

AF:

0.00439

Gnomad AMR exome

AF:

0.00973

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0270

Gnomad NFE exome

AF:

0.0224

Gnomad OTH exome

AF:

0.0189

GnomAD4 exome

AF:

0.0211

AC:

30682

AN:

1453468

Hom.:

406

Cov.:

AF XY:

0.0204

AC XY:

14751

AN XY:

722744

show subpopulations

African (AFR)

AF:

0.00346

AC:

115

AN:

33236

American (AMR)

AF:

0.0102

AC:

448

AN:

44128

Ashkenazi Jewish (ASJ)

AF:

0.0100

AC:

260

AN:

25912

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.00556

AC:

474

AN:

85178

European-Finnish (FIN)

AF:

0.0260

AC:

1375

AN:

52938

Middle Eastern (MID)

AF:

0.00320

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.0243

AC:

26928

AN:

1106988

Other (OTH)

AF:

0.0177

AC:

1064

AN:

60028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1373

2746

4119

5492

6865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0158

AC:

2392

AN:

151688

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1150

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.00455

AC:

189

AN:

41502

American (AMR)

AF:

0.0109

AC:

166

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

AN:

3452

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00436

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0270

AC:

286

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0246

AC:

1663

AN:

67582

Other (OTH)

AF:

0.0109

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

115

230

345

460

575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0196

Hom.:

Bravo

AF:

0.0137

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joubert syndrome 3

Benign:1

Jan 12, 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 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.9

(source)

DANN

Benign

0.80

PhyloP100

0.54

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00021

dbscSNV1_RF

Benign

0.012

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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rs41288015

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