NM_001134831.2:c.910dupA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001134831.2(AHI1):c.910dupA(p.Thr304AsnfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000853 in 1,559,732 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

AHI1
NM_001134831.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

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 16 ACMG points.

PVS1

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

PP5

Variant 6-135463145-G-GT is Pathogenic according to our data. Variant chr6-135463145-G-GT is described in ClinVar as Pathogenic. ClinVar VariationId is 217536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2 link	c.910dupA	p.Thr304AsnfsTer6	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.910dupA	p.Thr304AsnfsTer6	frameshift_variant	Exon 8 of 29	1	NM_001134831.2	ENSP00000265602.6		Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.0000202

AC:

AN:

148526

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000298

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000159

AC:

AN:

207782

AF XY:

0.000167

show subpopulations

Gnomad AFR exome

AF:

0.000154

Gnomad AMR exome

AF:

0.000264

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000715

Gnomad FIN exome

AF:

0.000268

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.000617

GnomAD4 exome

AF:

0.0000921

AC:

130

AN:

1411206

Hom.:

Cov.:

AF XY:

0.0000929

AC XY:

AN XY:

699774

show subpopulations

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

African (AFR)

AF:

0.000161

AC:

AN:

31106

American (AMR)

AF:

0.000100

AC:

AN:

39884

Ashkenazi Jewish (ASJ)

AF:

0.000161

AC:

AN:

24904

East Asian (EAS)

AF:

0.0000263

AC:

AN:

37976

South Asian (SAS)

AF:

0.000159

AC:

AN:

75468

European-Finnish (FIN)

AF:

0.000198

AC:

AN:

50406

Middle Eastern (MID)

AF:

0.000375

AC:

AN:

5328

European-Non Finnish (NFE)

AF:

0.0000800

AC:

AN:

1088102

Other (OTH)

AF:

0.0000862

AC:

AN:

58032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.324

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000202

AC:

AN:

148526

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

72254

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40230

American (AMR)

AF:

0.00

AC:

AN:

14764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3430

East Asian (EAS)

AF:

0.000197

AC:

AN:

5080

South Asian (SAS)

AF:

0.00

AC:

AN:

4572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000298

AC:

AN:

67062

Other (OTH)

AF:

0.00

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.00109

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 3

Pathogenic:4

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2020

Breda Genetics srl

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant c.910dupA (p.Thr304Asnfs*6) is reported as pathogenic for Joubert syndrome 3 in ClinVar (Variation ID: 217536). The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 6 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is present in gnomAD with an estimated allele frequency of 0.0001588, with no homozygous individuals reported. However, this variant was filtered out the gnomAD database because of it is found in a low complexity region and failed the random forest filters, due to presence of a poli-T stretch. Chafai-Elalaoui et al. (2015) reported the pathogenic variant c.910dupA (p.Thr304Asnfs*6) in the homozygous state in 3 affected sibling of a Moroccan family with Joubert syndrome (PMID: 26541515). The same mutation had already been reported by Kroes et al. (2008) in two Dutch patients in the compound heterozygous state (PMID: 18054307). -

Mar 01, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PM2,PM3 -

Joubert syndrome

Pathogenic:1

Mar 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Thr304Asnfs*6) in the AHI1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AHI1 are known to be pathogenic (PMID: 15322546, 16453322, 28442542, 29186038). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 16453322, 28431631). This variant is also known as c.903insA and c.903_910insA. ClinVar contains an entry for this variant (Variation ID: 217536). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Oct 04, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29186038, 28442542, 15322546, 26541515, 28431631, 33691693, 29974258, 26092869, 16453322) -

Joubert syndrome and related disorders

Pathogenic:1

Nov 25, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AHI1 c.910dupA (p.Thr304AsnfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 147308 control chromosomes (gnomAD, v3.1). c.910dupA has been reported in the literature as a biallelic genotype in multiple individuals affected with Joubert Syndrome And Related Disorders (e.g. Valente_2006, Chafai-Elalaoui_2015). These data indicate that the variant is very likely to be associated with disease. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinal dystrophy

Pathogenic:1

Jan 01, 2019

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.50

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over