6-135457656-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001134831.2(AHI1):c.989A>G(p.Asp330Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,930 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D330V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00076 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

AHI1
NM_001134831.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 1.60

Publications

5 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 -9 ACMG points.

BP6

Variant 6-135457656-T-C is Benign according to our data. Variant chr6-135457656-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215522.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000762 (116/152282) while in subpopulation AMR AF = 0.00177 (27/15296). AF 95% confidence interval is 0.00125. There are 1 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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.989A>G	p.Asp330Gly	missense	Exon 9 of 29	NP_001128303.1
AHI1	NM_001134830.2		c.989A>G	p.Asp330Gly	missense	Exon 7 of 27	NP_001128302.1
AHI1	NM_001350503.2		c.989A>G	p.Asp330Gly	missense	Exon 9 of 29	NP_001337432.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AHI1	ENST00000265602.11	TSL:1 MANE Select	c.989A>G	p.Asp330Gly	missense	Exon 9 of 29	ENSP00000265602.6
AHI1	ENST00000367800.8	TSL:1	c.989A>G	p.Asp330Gly	missense	Exon 7 of 27	ENSP00000356774.4
AHI1	ENST00000457866.6	TSL:1	c.989A>G	p.Asp330Gly	missense	Exon 8 of 28	ENSP00000388650.2

Frequencies

GnomAD3 genomes

AF:

0.000762

AC:

116

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000871

AC:

217

AN:

249204

AF XY:

0.000725

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00125

AC:

1825

AN:

1461648

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

822

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33478

American (AMR)

AF:

0.00233

AC:

104

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00148

AC:

1646

AN:

1111842

Other (OTH)

AF:

0.000928

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

190

285

380

475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.000762

AC:

116

AN:

152282

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41554

American (AMR)

AF:

0.00177

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00107

AC:

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

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:

0.000972

Hom.:

Bravo

AF:

0.000801

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00109

AC:

ExAC

AF:

0.000869

AC:

105

EpiCase

AF:

0.00115

EpiControl

AF:

0.00101

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Joubert syndrome 3 (2)

not provided (2)

AHI1-related disorder (1)

Inborn genetic diseases (1)

Joubert syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Benign

0.075

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.062

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.69

PhyloP100

1.6

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.3

REVEL

Benign

0.16

Sift

Uncertain

0.017

Sift4G

Uncertain

0.024

Polyphen

0.48

Vest4

0.34

MVP

0.62

MPC

0.17

ClinPred

0.015

GERP RS

5.5

PromoterAI

0.0098

Neutral

(source)

Varity_R

0.19

gMVP

0.17

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.35

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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