rs41288015

chr6-135427313-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134831.2(AHI1):c.2624-6A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,605,156 control chromosomes in the GnomAD database, including 443 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (37 hom., cov: 32)
  • Exomes 𝑓: 0.021 (406 hom.)
• Consequence: AHI1 NM_001134831.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002084
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.540

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=-0.65).
• BP6: Variant 6-135427313-T-C is Benign according to our data. Variant chr6-135427313-T-C is described in ClinVar as [Benign]. Clinvar id is 128325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135427313-T-C is described in Lovd as [Benign]. Variant chr6-135427313-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0158 (2392/151688) while in subpopulation NFE AF= 0.0246 (1663/67582). AF 95% confidence interval is 0.0236. There are 37 homozygotes in gnomad4. There are 1150 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.2624-6A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.2624-6A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2393 AN: 151570 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00457

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0116

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0270

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0156 AC: 3740 AN: 239992 Hom.: 41 AF XY: 0.0151 AC XY: 1969 AN XY: 130210

Gnomad AFR exome AF: 0.00439

Gnomad AMR exome AF: 0.00973

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00483

Gnomad FIN exome AF: 0.0270

Gnomad NFE exome AF: 0.0224

Gnomad OTH exome AF: 0.0189

GnomAD4 exome AF: 0.0211 AC: 30682 AN: 1453468 Hom.: 406 Cov.: 30 AF XY: 0.0204 AC XY: 14751 AN XY: 722744

Gnomad4 AFR exome AF: 0.00346

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00556

Gnomad4 FIN exome AF: 0.0260

Gnomad4 NFE exome AF: 0.0243

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0158 AC: 2392 AN: 151688 Hom.: 37 Cov.: 32 AF XY: 0.0155 AC XY: 1150 AN XY: 74178

Gnomad4 AFR AF: 0.00455

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0116

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.0270

Gnomad4 NFE AF: 0.0246

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0218 Hom.: 13

Bravo AF: 0.0137

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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. -

Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	7.9
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.012
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: rs41288015; hg19: chr6-135748451;