rs2273761

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_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. In-silico tool predicts a benign outcome for this variant. 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 6-135433070-A-G is Benign according to our data. Variant chr6-135433070-A-G is described in ClinVar 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 Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 63 AR 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

GnomAD3 exomes

AF:

0.0241

AC:

6006

AN:

248980

Hom.:

137

AF XY:

0.0248

AC XY:

3344

AN XY:

135048

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 SAS exome

AF:

0.0404

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

Gnomad4 AFR exome

AF:

0.0351

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.0189

Gnomad4 EAS exome

AF:

0.0429

Gnomad4 SAS exome

AF:

0.0415

Gnomad4 FIN exome

AF:

0.0192

Gnomad4 NFE exome

AF:

0.0182

Gnomad4 OTH exome

AF:

0.0267

GnomAD4 genome

AF:

0.0243

AC:

3703

AN:

152296

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

1839

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0362

Gnomad4 AMR

AF:

0.0167

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.0542

Gnomad4 SAS

AF:

0.0333

Gnomad4 FIN

AF:

0.0208

Gnomad4 NFE

AF:

0.0172

Gnomad4 OTH

AF:

0.0251

Alfa

AF:

0.0191

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 25, 2013

Genetic Services Laboratory, University of Chicago

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

- -

Familial aplasia of the vermis

Benign:1

Feb 03, 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

-0.70

CADD

Benign

2.2

DANN

Benign

0.42

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over