Genetic Variant AHI1:p.Thr304LysfsTer24 (chr6-135463145-G-GTT) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001134831.2(AHI1):c.909_910dupAA(p.Thr304LysfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000673 in 148,530 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AHI1
NM_001134831.2 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.503

Publications

11 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: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2 link	c.909_910dupAA	p.Thr304LysfsTer24	frameshift_variant	Exon 8 of 29	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.909_910dupAA	p.Thr304LysfsTer24	frameshift_variant	Exon 8 of 29	1	NM_001134831.2	ENSP00000265602.6		Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.00000673

AC:

AN:

148530

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1411910

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700154

African (AFR)

AF:

0.00

AC:

AN:

31138

American (AMR)

AF:

0.00

AC:

AN:

39918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24922

East Asian (EAS)

AF:

0.00

AC:

AN:

38016

South Asian (SAS)

AF:

0.00

AC:

AN:

75584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5330

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088494

Other (OTH)

AF:

0.00

AC:

AN:

58074

GnomAD4 genome

AF:

0.00000673

AC:

AN:

148530

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72258

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000249

AC:

AN:

40232

American (AMR)

AF:

0.00

AC:

AN:

14764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.00

AC:

AN:

5080

South Asian (SAS)

AF:

0.00

AC:

AN:

4572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67062

Other (OTH)

AF:

0.00

AC:

AN:

2016

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.50

Mutation Taster

=10/190

disease causing (fs/PTC)

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over