Genetic Variant NM_001134831.2:c.3546G>A (chr6-135290465-C-T) – ACMG Classification: Benign (-20 pts)

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.3546G>A(p.Met1182Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,613,404 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 2 hom. )

Consequence

AHI1
NM_001134831.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.195

Publications

0 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:

ENSG00000234084 (HGNC:):

ENSG00000234084 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=0.004057497).

BP6

Variant 6-135290465-C-T is Benign according to our data. Variant chr6-135290465-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 286680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00209 (319/152308) while in subpopulation AFR AF = 0.00743 (309/41570). AF 95% confidence interval is 0.00675. There are 2 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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.3546G>A	p.Met1182Ile	missense	Exon 28 of 29	NP_001128303.1
AHI1	NM_001134830.2		c.3546G>A	p.Met1182Ile	missense	Exon 26 of 27	NP_001128302.1
AHI1	NM_001350503.2		c.3546G>A	p.Met1182Ile	missense	Exon 28 of 29	NP_001337432.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AHI1	ENST00000265602.11	TSL:1 MANE Select	c.3546G>A	p.Met1182Ile	missense	Exon 28 of 29	ENSP00000265602.6
AHI1	ENST00000367800.8	TSL:1	c.3546G>A	p.Met1182Ile	missense	Exon 26 of 27	ENSP00000356774.4
AHI1	ENST00000457866.6	TSL:1	c.3546G>A	p.Met1182Ile	missense	Exon 27 of 28	ENSP00000388650.2

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00743

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.00

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000490

AC:

121

AN:

246790

AF XY:

0.000343

show subpopulations

Gnomad AFR exome

AF:

0.00684

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000204

AC:

298

AN:

1461096

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

726886

show subpopulations

African (AFR)

AF:

0.00780

AC:

261

AN:

33466

American (AMR)

AF:

0.000313

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111328

Other (OTH)

AF:

0.000348

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00209

AC:

319

AN:

152308

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00743

AC:

309

AN:

41570

American (AMR)

AF:

0.000523

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000743

Hom.:

Bravo

AF:

0.00244

ESP6500AA

AF:

0.00629

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000604

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

AHI1-related disorder (1)

Joubert syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.60

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.069

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.43

M_CAP

Benign

0.0069

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-0.20

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.020

REVEL

Benign

0.043

Sift

Benign

0.73

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.15

MutPred

0.17

Loss of catalytic residue at M1182 (P = 0.0905)

MVP

0.30

MPC

0.045

ClinPred

0.00012

GERP RS

0.43

Varity_R

0.056

gMVP

0.21

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

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

Computational scores

Splicing

Publications

Other links and lift over