rs9494209

Positions:

• chr6-135285617-C-G
• chr6-135285617-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001134831.2(AHI1):​c.*28G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,602,404 control chromosomes in the GnomAD database, including 6,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1583 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4640 hom.)
• Consequence: AHI1 NM_001134831.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.575

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-135285617-C-G is Benign according to our data. Variant chr6-135285617-C-G is described in ClinVar as [Benign]. Clinvar id is 260835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135285617-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.*28G>C		3_prime_UTR_variant	29/29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.*28G>C		3_prime_UTR_variant	29/29	1	NM_001134831.2	ENSP00000265602	P2

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17652 AN: 152076 Hom.: 1572 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0844

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.0673

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0243

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0666

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.0730 AC: 17639 AN: 241654 Hom.: 994 AF XY: 0.0711 AC XY: 9319 AN XY: 131110

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.0688

Gnomad ASJ exome AF: 0.0268

Gnomad EAS exome AF: 0.0610

Gnomad SAS exome AF: 0.0955

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0614

Gnomad OTH exome AF: 0.0622

GnomAD4 exome AF: 0.0708 AC: 102717 AN: 1450210 Hom.: 4640 Cov.: 29 AF XY: 0.0707 AC XY: 51028 AN XY: 721362

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.0715

Gnomad4 ASJ exome AF: 0.0286

Gnomad4 EAS exome AF: 0.0807

Gnomad4 SAS exome AF: 0.0986

Gnomad4 FIN exome AF: 0.0281

Gnomad4 NFE exome AF: 0.0654

Gnomad4 OTH exome AF: 0.0775

GnomAD4 genome AF: 0.116 AC: 17703 AN: 152194 Hom.: 1583 Cov.: 32 AF XY: 0.112 AC XY: 8331 AN XY: 74422

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.0841

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.0673

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.0243

Gnomad4 NFE AF: 0.0666

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0385 Hom.: 43

Bravo AF: 0.125

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Joubert syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.8
DANN	Benign	0.59

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: rs9494209; hg19: chr6-135606755; COSMIC: COSV55624645;