6-135466046-C-T

Position:

chr6-135466046-C-T

Variant summary

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

The ENST00000265602.11(AHI1):c.517G>A(p.Ala173Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,613,882 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 17 hom. )

Consequence

AHI1
ENST00000265602.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.154

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=0.002779305).

BP6

Variant 6-135466046-C-T is Benign according to our data. Variant chr6-135466046-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 166664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135466046-C-T is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHI1	NM_001134831.2 linkuse as main transcript	c.517G>A	p.Ala173Thr	missense_variant	7/29	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.517G>A	p.Ala173Thr	missense_variant	7/29	1	NM_001134831.2	ENSP00000265602	P2	Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.00337

AC:

512

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0175

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00357

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00405

AC:

1010

AN:

249150

Hom.:

AF XY:

0.00430

AC XY:

581

AN XY:

135168

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.0189

Gnomad NFE exome

AF:

0.00406

Gnomad OTH exome

AF:

0.00611

GnomAD4 exome

AF:

0.00293

AC:

4288

AN:

1461642

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

2248

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.00268

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00143

Gnomad4 FIN exome

AF:

0.0172

Gnomad4 NFE exome

AF:

0.00255

Gnomad4 OTH exome

AF:

0.00345

GnomAD4 genome

AF:

0.00336

AC:

512

AN:

152240

Hom.:

Cov.:

AF XY:

0.00390

AC XY:

290

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0175

Gnomad4 NFE

AF:

0.00357

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00319

Hom.:

Bravo

AF:

0.00225

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000517

AC:

ESP6500EA

AF:

0.00327

AC:

ExAC

AF:

0.00397

AC:

480

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00409

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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)	Mar 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	AHI1: BP4, BS2 -

Joubert syndrome 3

Benign:1

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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

0.067

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

2.4

DANN

Benign

0.95

DEOGEN2

Benign

0.085

T;T;T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.63

.;.;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.97

L;L;L;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.39

N;N;N;N;N

REVEL

Benign

0.034

Sift

Benign

0.56

T;T;T;T;T

Sift4G

Benign

0.57

T;T;T;T;.

Polyphen

0.024

B;B;B;B;.

Vest4

0.14

MVP

0.32

MPC

0.041

ClinPred

0.00056

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.020

gMVP

0.053

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