rs117447608

Positions:

chr6-135318577-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000265602.11(AHI1):c.3368C>T(p.Ser1123Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,605,928 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 49 hom. )

Consequence

AHI1
ENST00000265602.11 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.18

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011013359).

BP6

Variant 6-135318577-G-A is Benign according to our data. Variant chr6-135318577-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135318577-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHI1	NM_001134831.2 linkuse as main transcript	c.3368C>T	p.Ser1123Phe	missense_variant	26/29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11 linkuse as main transcript	c.3368C>T	p.Ser1123Phe	missense_variant	26/29	1	NM_001134831.2	ENSP00000265602	P2	Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.00477

AC:

726

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00869

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00524

AC:

1239

AN:

236492

Hom.:

AF XY:

0.00542

AC XY:

693

AN XY:

127746

show subpopulations

Gnomad AFR exome

AF:

0.00118

Gnomad AMR exome

AF:

0.000993

Gnomad ASJ exome

AF:

0.00175

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00207

Gnomad FIN exome

AF:

0.00483

Gnomad NFE exome

AF:

0.00918

Gnomad OTH exome

AF:

0.00532

GnomAD4 exome

AF:

0.00733

AC:

10654

AN:

1453612

Hom.:

Cov.:

AF XY:

0.00726

AC XY:

5239

AN XY:

721984

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.00155

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00220

Gnomad4 FIN exome

AF:

0.00506

Gnomad4 NFE exome

AF:

0.00876

Gnomad4 OTH exome

AF:

0.00597

GnomAD4 genome

AF:

0.00477

AC:

726

AN:

152316

Hom.:

Cov.:

AF XY:

0.00463

AC XY:

345

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00546

Gnomad4 NFE

AF:

0.00869

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00739

Hom.:

Bravo

AF:

0.00431

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00302

AC:

ESP6500EA

AF:

0.00808

AC:

ExAC

AF:

0.00574

AC:

693

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 03, 2022	Variant summary: AHI1 c.3368C>T (p.Ser1123Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0052 in 236492 control chromosomes, predominantly at a frequency of 0.0092 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in AHI1 causing Joubert Syndrome And Related Disorders phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=5) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	AHI1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -

Joubert syndrome 3

Benign:2

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Joubert syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BS4 => Lack of segregation in affected members of a family (PMID:16453322). -

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

0.10

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

.;.;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.97

L;L;L

MutationTaster

Benign

0.57

D;D;D;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.27

Sift

Uncertain

0.0040

D;D;D

Sift4G

Benign

0.29

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.61

MVP

0.70

MPC

0.25

ClinPred

0.013

GERP RS

5.2

Varity_R

0.13

gMVP

0.25

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