chr6-135455872-AG-A

Variant names:

• chr6-135455872-AG-A
• rs794729195
• NM_001134831.2:c.1205delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001134831.2(AHI1):​c.1205delC​(p.Pro402LeufsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,433,836 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60
• Publications: 1 publications found

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, Laboratory for Molecular Medicine, ClinGen, 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

ACMG classification

Our verdict: Pathogenic. The variant received 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 6-135455872-AG-A is Pathogenic according to our data. Variant chr6-135455872-AG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 202167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	NM_001134831.2	MANE Select	c.1205delC	p.Pro402LeufsTer3	frameshift	Exon 10 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.1205delC	p.Pro402LeufsTer3	frameshift	Exon 8 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.1205delC	p.Pro402LeufsTer3	frameshift	Exon 10 of 29	NP_001337432.1	Q8N157-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHI1	ENST00000265602.11	TSL:1 MANE Select	c.1205delC	p.Pro402LeufsTer3	frameshift	Exon 10 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.1205delC	p.Pro402LeufsTer3	frameshift	Exon 8 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.1205delC	p.Pro402LeufsTer3	frameshift	Exon 9 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1433836 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 709826

African (AFR) AF: 0.00 AC: 0 AN: 32980

American (AMR) AF: 0.0000233 AC: 1 AN: 42962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25426

East Asian (EAS) AF: 0.00 AC: 0 AN: 39228

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094212

Other (OTH) AF: 0.0000169 AC: 1 AN: 59174

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Joubert syndrome (1)
1	-	-	Joubert syndrome 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794729195; hg19: chr6-135777010;