rs1052502

Positions:

• chr6-135285427-G-A

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.*218C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 595,260 control chromosomes in the GnomAD database, including 16,330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (11555 hom., cov: 32)
  • Exomes 𝑓: 0.095 (4775 hom.)
• Consequence: AHI1 NM_001134831.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.113

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=-0.87).
• BP6: Variant 6-135285427-G-A is Benign according to our data. Variant chr6-135285427-G-A is described in ClinVar as [Benign]. Clinvar id is 355491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.*218C>T		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.*218C>T		3_prime_UTR_variant	29/29	1	NM_001134831.2	ENSP00000265602	P2

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39462 AN: 152024 Hom.: 11505 Cov.: 32

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0735

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.0946 AC: 41915 AN: 443118 Hom.: 4775 Cov.: 4 AF XY: 0.0914 AC XY: 21467 AN XY: 234942

Gnomad4 AFR exome AF: 0.717

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.0563

Gnomad4 EAS exome AF: 0.117

Gnomad4 SAS exome AF: 0.0960

Gnomad4 FIN exome AF: 0.0296

Gnomad4 NFE exome AF: 0.0688

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.260 AC: 39573 AN: 152142 Hom.: 11555 Cov.: 32 AF XY: 0.252 AC XY: 18725 AN XY: 74392

Gnomad4 AFR AF: 0.725

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.0559

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0735

Gnomad4 OTH AF: 0.238

Alfa AF: 0.100 Hom.: 4046

Bravo AF: 0.291

Asia WGS AF: 0.199 AC: 694 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.91
DANN	Benign	0.60

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: rs1052502; hg19: chr6-135606565; COSMIC: COSV55634852;