rs2273761

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_StrongBP7BS1BS2

The NM_001134831.2(AHI1):c.2223T>C(p.Asp741Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,613,536 control chromosomes in the GnomAD database, including 521 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 63 hom., cov: 32)

Exomes 𝑓: 0.021 ( 458 hom. )

Consequence

AHI1
NM_001134831.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.00500

Publications

10 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 -17 ACMG points.

BP6

Variant 6-135433070-A-G is Benign according to our data. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in CliVar as Benign. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.005 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0243 (3703/152296) while in subpopulation EAS AF = 0.0542 (281/5186). AF 95% confidence interval is 0.049. There are 63 homozygotes in GnomAd4. There are 1839 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 63 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2 link	c.2223T>C	p.Asp741Asp	synonymous_variant	Exon 16 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.2223T>C	p.Asp741Asp	synonymous_variant	Exon 16 of 29	1	NM_001134831.2	ENSP00000265602.6		Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

3696

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0362

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0167

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0537

Gnomad SAS

AF:

0.0331

Gnomad FIN

AF:

0.0208

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0258

GnomAD2 exomes

AF:

0.0241

AC:

6006

AN:

248980

AF XY:

0.0248

show subpopulations

Gnomad AFR exome

AF:

0.0386

Gnomad AMR exome

AF:

0.00997

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.0629

Gnomad FIN exome

AF:

0.0184

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.0230

GnomAD4 exome

AF:

0.0208

AC:

30418

AN:

1461240

Hom.:

458

Cov.:

AF XY:

0.0215

AC XY:

15630

AN XY:

726938

show subpopulations

African (AFR)

AF:

0.0351

AC:

1173

AN:

33454

American (AMR)

AF:

0.0110

AC:

492

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0189

AC:

493

AN:

26126

East Asian (EAS)

AF:

0.0429

AC:

1699

AN:

39618

South Asian (SAS)

AF:

0.0415

AC:

3582

AN:

86246

European-Finnish (FIN)

AF:

0.0192

AC:

1023

AN:

53394

Middle Eastern (MID)

AF:

0.0158

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0182

AC:

20255

AN:

1111566

Other (OTH)

AF:

0.0267

AC:

1610

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1574

3149

4723

6298

7872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.0243

AC:

3703

AN:

152296

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

1839

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0362

AC:

1504

AN:

41556

American (AMR)

AF:

0.0167

AC:

255

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.0542

AC:

281

AN:

5186

South Asian (SAS)

AF:

0.0333

AC:

161

AN:

4830

European-Finnish (FIN)

AF:

0.0208

AC:

221

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1172

AN:

68020

Other (OTH)

AF:

0.0251

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

183

366

550

733

916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0202

Hom.:

Bravo

AF:

0.0256

Asia WGS

AF:

0.0450

AC:

157

AN:

3476

EpiCase

AF:

0.0186

EpiControl

AF:

0.0186

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome 3

Benign:1

Jan 13, 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. -

not provided

Benign:1

Mar 03, 2015

GeneDx

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

-0.70

CADD

Benign

2.2

(source)

DANN

Benign

0.42

PhyloP100

0.0050

Mutation Taster

=100/0

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