rs2757645

chr6-135442728-G-Achr6-135442728-G-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.1780-14C>T variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.916 in 1,582,822 control chromosomes in the GnomAD database, including 669,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (54399 hom., cov: 33)
  • Exomes 𝑓: 0.93 (615565 hom.)
• Consequence: AHI1 NM_001134831.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.12

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=-0.92).
• BP6: Variant 6-135442728-G-A is Benign according to our data. Variant chr6-135442728-G-A is described in ClinVar as [Benign]. Clinvar id is 260839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135442728-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.1780-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.1780-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.828 AC: 125940 AN: 152058 Hom.: 54380 Cov.: 33

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.968

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.955

Gnomad EAS AF: 0.965

Gnomad SAS AF: 0.948

Gnomad FIN AF: 0.976

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.844

GnomAD3 exomes AF: 0.915 AC: 209365 AN: 228880 Hom.: 96920 AF XY: 0.922 AC XY: 114473 AN XY: 124192

Gnomad AFR exome AF: 0.539

Gnomad AMR exome AF: 0.916

Gnomad ASJ exome AF: 0.954

Gnomad EAS exome AF: 0.971

Gnomad SAS exome AF: 0.948

Gnomad FIN exome AF: 0.973

Gnomad NFE exome AF: 0.931

Gnomad OTH exome AF: 0.927

GnomAD4 exome AF: 0.926 AC: 1324168 AN: 1430646 Hom.: 615565 Cov.: 34 AF XY: 0.927 AC XY: 658276 AN XY: 709742

Gnomad4 AFR exome AF: 0.545

Gnomad4 AMR exome AF: 0.911

Gnomad4 ASJ exome AF: 0.955

Gnomad4 EAS exome AF: 0.966

Gnomad4 SAS exome AF: 0.948

Gnomad4 FIN exome AF: 0.970

Gnomad4 NFE exome AF: 0.932

Gnomad4 OTH exome AF: 0.909

GnomAD4 genome AF: 0.828 AC: 126009 AN: 152176 Hom.: 54399 Cov.: 33 AF XY: 0.834 AC XY: 62061 AN XY: 74412

Gnomad4 AFR AF: 0.552

Gnomad4 AMR AF: 0.891

Gnomad4 ASJ AF: 0.955

Gnomad4 EAS AF: 0.965

Gnomad4 SAS AF: 0.947

Gnomad4 FIN AF: 0.976

Gnomad4 NFE AF: 0.931

Gnomad4 OTH AF: 0.844

Alfa AF: 0.891 Hom.: 7446

Bravo AF: 0.811

Asia WGS AF: 0.904 AC: 3144 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Joubert syndrome 3 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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

Mar 03, 2015

- -

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	-0.92
Cadd	Benign	11
Dann	Benign	0.78

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: rs2757645; hg19: chr6-135763866;