Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001134831.2(AHI1):c.2798A>G(p.Tyr933Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,604,136 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y933H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0045 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 25 hom. )

Consequence

AHI1
NM_001134831.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.499

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009422123).

BP6

Variant 6-135411511-T-C is Benign according to our data. Variant chr6-135411511-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0045 (685/152292) while in subpopulation NFE AF = 0.00653 (444/68026). AF 95% confidence interval is 0.00603. There are 1 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 25 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134831.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AHI1	NM_001134831.2	MANE Select	c.2798A>G	p.Tyr933Cys	missense	Exon 21 of 29	NP_001128303.1
AHI1	NM_001134830.2		c.2798A>G	p.Tyr933Cys	missense	Exon 19 of 27	NP_001128302.1
AHI1	NM_001350503.2		c.2798A>G	p.Tyr933Cys	missense	Exon 21 of 29	NP_001337432.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AHI1	ENST00000265602.11	TSL:1 MANE Select	c.2798A>G	p.Tyr933Cys	missense	Exon 21 of 29	ENSP00000265602.6
AHI1	ENST00000367800.8	TSL:1	c.2798A>G	p.Tyr933Cys	missense	Exon 19 of 27	ENSP00000356774.4
AHI1	ENST00000457866.6	TSL:1	c.2798A>G	p.Tyr933Cys	missense	Exon 20 of 28	ENSP00000388650.2

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

686

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00654

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00407

AC:

992

AN:

243656

AF XY:

0.00423

show subpopulations

Gnomad AFR exome

AF:

0.00240

Gnomad AMR exome

AF:

0.00410

Gnomad ASJ exome

AF:

0.00163

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.00659

Gnomad OTH exome

AF:

0.00492

GnomAD4 exome

AF:

0.00486

AC:

7062

AN:

1451844

Hom.:

Cov.:

AF XY:

0.00493

AC XY:

3555

AN XY:

720864

show subpopulations

African (AFR)

AF:

0.00313

AC:

104

AN:

33184

American (AMR)

AF:

0.00476

AC:

208

AN:

43668

Ashkenazi Jewish (ASJ)

AF:

0.00174

AC:

AN:

25844

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.00159

AC:

134

AN:

84306

European-Finnish (FIN)

AF:

0.000338

AC:

AN:

53180

Middle Eastern (MID)

AF:

0.00858

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00565

AC:

6253

AN:

1106444

Other (OTH)

AF:

0.00419

AC:

251

AN:

59976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

344

688

1031

1375

1719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

226

452

678

904

1130

<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:

0.00450

AC:

685

AN:

152292

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

330

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41552

American (AMR)

AF:

0.00556

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00145

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00653

AC:

444

AN:

68026

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00554

Hom.:

Bravo

AF:

0.00479

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00107

AC:

ESP6500EA

AF:

0.00619

AC:

ExAC

AF:

0.00389

AC:

470

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Joubert syndrome (1)

Joubert syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.032

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.76

M_CAP

Benign

0.0034

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

0.50

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.6

REVEL

Benign

0.16

Sift

Benign

0.037

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.39

MVP

0.59

MPC

0.055

ClinPred

0.041

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.23

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs41288013

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over