rs863225131

Positions:

• chr6-135428757-A-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001134831.2(AHI1):​c.2495T>G​(p.Leu832*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AHI1 NM_001134831.2 stop_gained, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.72

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant 6-135428757-A-C is Pathogenic according to our data. Variant chr6-135428757-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135428757-A-C is described in Lovd as [Pathogenic]. Variant chr6-135428757-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.2495T>G	p.Leu832*	stop_gained, splice_region_variant	19/29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.2495T>G	p.Leu832*	stop_gained, splice_region_variant	19/29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447062 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718676

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UW Hindbrain Malformation Research Program, University of Washington

Feb 23, 2015

- -

Joubert syndrome and related disorders Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 06, 2023

Variant summary: AHI1 c.2495T>G (p.Leu832X) 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. Truncations downstream of this position have been classified as pathogenic in ClinVar and are associated with Joubert syndrome in HGMD. The variant was absent in 231274 control chromosomes. c.2495T>G has been reported in the literature in at least one individual affected with Joubert Syndrome (e.g., Parisi_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) has cited the variant and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	1.0	D
Vest4		0.93
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs863225131; hg19: chr6-135749895;