rs13197384

chr6-135497759-C-Achr6-135497759-C-T

Variant summary

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

The ENST00000457866.6(AHI1):c.-293G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 199,288 control chromosomes in the GnomAD database, including 11,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7142 hom., cov: 33)
  • Exomes 𝑓: 0.40 (3920 hom.)
• Consequence: AHI1 ENST00000457866.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.45

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-DT (HGNC:32526): (AHI1 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 6-135497759-C-A is Benign according to our data. Variant chr6-135497759-C-A is described in ClinVar as [Benign]. Clinvar id is 355518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135497759-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2			upstream_gene_variant		ENST00000265602.11
AHI1-DT	NR_152842.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11			upstream_gene_variant		1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45583 AN: 152066 Hom.: 7135 Cov.: 33

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.307

GnomAD3 exomes AF: 0.397 AC: 282 AN: 710 Hom.: 57 AF XY: 0.426 AC XY: 173 AN XY: 406

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.450

Gnomad EAS exome AF: 0.357

Gnomad SAS exome AF: 0.533

Gnomad FIN exome AF: 0.550

Gnomad NFE exome AF: 0.412

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.399 AC: 18801 AN: 47106 Hom.: 3920 Cov.: 0 AF XY: 0.406 AC XY: 11816 AN XY: 29084

Gnomad4 AFR exome AF: 0.264

Gnomad4 AMR exome AF: 0.268

Gnomad4 ASJ exome AF: 0.407

Gnomad4 EAS exome AF: 0.298

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.380

Gnomad4 OTH exome AF: 0.405

GnomAD4 genome AF: 0.300 AC: 45615 AN: 152182 Hom.: 7142 Cov.: 33 AF XY: 0.299 AC XY: 22234 AN XY: 74412

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.297

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.349

Gnomad4 OTH AF: 0.310

Alfa AF: 0.272 Hom.: 1262

Bravo AF: 0.293

Asia WGS AF: 0.317 AC: 1103 AN: 3476

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 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

Jan 28, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	11
Dann	Benign	0.81

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13197384; hg19: chr6-135818897; COSMIC: COSV55628646; COSMIC: COSV55628646;