6-135463145-GTTT-GTTTT

Variant names:

• chr6-135463145-G-GT
• rs753874898
• NM_001134831.2:c.910dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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 Likely 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.503
• Publications: 11 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 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/Likely_pathogenic. ClinVar VariationId is 217536.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.910dupA	p.Thr304AsnfsTer6	frameshift	Exon 8 of 29	NP_001128303.1	Q8N157-1
	AHI1	NM_001134830.2		c.910dupA	p.Thr304AsnfsTer6	frameshift	Exon 6 of 27	NP_001128302.1	Q8N157-1
	AHI1	NM_001350503.2		c.910dupA	p.Thr304AsnfsTer6	frameshift	Exon 8 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.910dupA	p.Thr304AsnfsTer6	frameshift	Exon 8 of 29	ENSP00000265602.6	Q8N157-1
	AHI1	ENST00000367800.8	TSL:1	c.910dupA	p.Thr304AsnfsTer6	frameshift	Exon 6 of 27	ENSP00000356774.4	Q8N157-1
	AHI1	ENST00000457866.6	TSL:1	c.910dupA	p.Thr304AsnfsTer6	frameshift	Exon 7 of 28	ENSP00000388650.2	Q8N157-1

Frequencies

GnomAD3 genomes AF: 0.0000202 AC: 3 AN: 148526 Hom.: 0 Cov.: 30

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: 33 AN: 207782 AF XY: 0.000167

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.: 0 Cov.: 31 AF XY: 0.0000929 AC XY: 65 AN XY: 699774

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

African (AFR) AF: 0.000161 AC: 5 AN: 31106

American (AMR) AF: 0.000100 AC: 4 AN: 39884

Ashkenazi Jewish (ASJ) AF: 0.000161 AC: 4 AN: 24904

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 37976

South Asian (SAS) AF: 0.000159 AC: 12 AN: 75468

European-Finnish (FIN) AF: 0.000198 AC: 10 AN: 50406

Middle Eastern (MID) AF: 0.000375 AC: 2 AN: 5328

European-Non Finnish (NFE) AF: 0.0000800 AC: 87 AN: 1088102

Other (OTH) AF: 0.0000862 AC: 5 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.

GnomAD4 genome AF: 0.0000202 AC: 3 AN: 148526 Hom.: 0 Cov.: 30 AF XY: 0.0000277 AC XY: 2 AN XY: 72254

African (AFR) AF: 0.00 AC: 0 AN: 40230

American (AMR) AF: 0.00 AC: 0 AN: 14764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000298 AC: 2 AN: 67062

Other (OTH) AF: 0.00 AC: 0 AN: 2016

Alfa AF: 0.00109 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Joubert syndrome 3 (4)
2	-	-	not provided (2)
1	-	-	Joubert syndrome (1)
1	-	-	Joubert syndrome and related disorders (1)
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.50
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs753874898; hg19: chr6-135784283; COSMIC: COSV55623018;