Genetic Variant AHI1:c.3166-4551G>A (chr6-135327875-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001134831.2(AHI1):c.3166-4551G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 152,062 control chromosomes in the GnomAD database, including 17,468 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.46 ( 17468 hom., cov: 31)

Consequence

AHI1
NM_001134831.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.298

Publications

8 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:

ENSG00000287094 (HGNC:):

ENSG00000287094 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2 link	c.3166-4551G>A		intron_variant	Intron 24 of 28	ENST00000265602.11	NP_001128303.1	Q8N157-1Q8NER0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11 link	c.3166-4551G>A		intron_variant	Intron 24 of 28	1	NM_001134831.2	ENSP00000265602.6		Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.458

AC:

69545

AN:

151946

Hom.:

17469

Cov.:

show subpopulations

Gnomad AFR

AF:

0.227

Gnomad AMI

AF:

0.665

Gnomad AMR

AF:

0.548

Gnomad ASJ

AF:

0.584

Gnomad EAS

AF:

0.566

Gnomad SAS

AF:

0.490

Gnomad FIN

AF:

0.597

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.535

Gnomad OTH

AF:

0.482

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.457

AC:

69553

AN:

152062

Hom.:

17468

Cov.:

AF XY:

0.464

AC XY:

34506

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.227

AC:

9395

AN:

41456

American (AMR)

AF:

0.548

AC:

8382

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.584

AC:

2027

AN:

3472

East Asian (EAS)

AF:

0.565

AC:

2931

AN:

5184

South Asian (SAS)

AF:

0.490

AC:

2359

AN:

4818

European-Finnish (FIN)

AF:

0.597

AC:

6313

AN:

10582

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.535

AC:

36351

AN:

67948

Other (OTH)

AF:

0.477

AC:

1010

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1804

3607

5411

7214

9018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

638

1276

1914

2552

3190

<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:

0.511

Hom.:

10368

Bravo

AF:

0.445

Asia WGS

AF:

0.503

AC:

1748

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.5

(source)

DANN

Benign

0.29

PhyloP100

0.30

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over