rs148000791

Positions:

chr6-135323233-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001134831.2(AHI1):c.3257A>G(p.Glu1086Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,910 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 43 hom. )

Consequence

AHI1
NM_001134831.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:13

Conservation

PhyloP100: 7.67

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:

AHI1 (HGNC:):

AHI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008024454).

BP6

Variant 6-135323233-T-C is Benign according to our data. Variant chr6-135323233-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143152.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=6, Likely_pathogenic=1}. Variant chr6-135323233-T-C is described in Lovd as [Benign]. Variant chr6-135323233-T-C is described in Lovd as [Likely_benign]. Variant chr6-135323233-T-C is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00173 (264/152290) while in subpopulation EAS AF= 0.0401 (208/5188). AF 95% confidence interval is 0.0356. There are 2 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHI1	NM_001134831.2 linkuse as main transcript	c.3257A>G	p.Glu1086Gly	missense_variant	25/29	ENST00000265602.11	NP_001128303.1	Q8N157-1Q8NER0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11 linkuse as main transcript	c.3257A>G	p.Glu1086Gly	missense_variant	25/29	1	NM_001134831.2	ENSP00000265602.6		Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.00174

AC:

265

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0402

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00377

AC:

938

AN:

249080

Hom.:

AF XY:

0.00349

AC XY:

472

AN XY:

135130

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0451

Gnomad SAS exome

AF:

0.000981

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.000407

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00150

AC:

2186

AN:

1461620

Hom.:

Cov.:

AF XY:

0.00146

AC XY:

1065

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0436

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.00159

Gnomad4 NFE exome

AF:

0.000146

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.00173

AC:

264

AN:

152290

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0401

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.00195

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.00378

AC:

457

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -

Joubert syndrome 3

Pathogenic:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Oct 04, 2021	East Asian population allele frequency is 4.5% (rs148000791, 874/19,504 alleles, 22 homozygotes in gnomAD v2.1). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, flagged submission	clinical testing	UCLA Clinical Genomics Center, UCLA	Nov 20, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	AHI1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 24690944, 27491411, 29343940, 22995991, 25356976, 21228398, 18054307, 26035799, 26035800, 22425360, 28976722, 28391287, 25326637, 31938409) -

Optic atrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 01, 2022

- -

Familial aplasia of the vermis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.16

T;T;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.75

.;.;T

MetaRNN

Benign

0.0080

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.86

L;L;L

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.42

MVP

0.60

MPC

0.31

ClinPred

0.062

GERP RS

6.1

Varity_R

0.69

gMVP

0.34

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