rs2273761

Positions:

• chr6-135433070-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001134831.2(AHI1):​c.2223T>C​(p.Asp741=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,613,536 control chromosomes in the GnomAD database, including 521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (63 hom., cov: 32)
  • Exomes 𝑓: 0.021 (458 hom.)
• Consequence: AHI1 NM_001134831.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.00500

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 6-135433070-A-G is Benign according to our data. Variant chr6-135433070-A-G is described in ClinVar as [Benign]. Clinvar id is 128323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135433070-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.005 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0243 (3703/152296) while in subpopulation EAS AF= 0.0542 (281/5186). AF 95% confidence interval is 0.049. There are 63 homozygotes in gnomad4. There are 1839 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.2223T>C	p.Asp741=	synonymous_variant	16/29	ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.2223T>C	p.Asp741=	synonymous_variant	16/29	1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3696 AN: 152178 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0537

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0241 AC: 6006 AN: 248980 Hom.: 137 AF XY: 0.0248 AC XY: 3344 AN XY: 135048

Gnomad AFR exome AF: 0.0386

Gnomad AMR exome AF: 0.00997

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.0629

Gnomad SAS exome AF: 0.0404

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0208 AC: 30418 AN: 1461240 Hom.: 458 Cov.: 31 AF XY: 0.0215 AC XY: 15630 AN XY: 726938

Gnomad4 AFR exome AF: 0.0351

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.0429

Gnomad4 SAS exome AF: 0.0415

Gnomad4 FIN exome AF: 0.0192

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0267

GnomAD4 genome AF: 0.0243 AC: 3703 AN: 152296 Hom.: 63 Cov.: 32 AF XY: 0.0247 AC XY: 1839 AN XY: 74478

Gnomad4 AFR AF: 0.0362

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.0542

Gnomad4 SAS AF: 0.0333

Gnomad4 FIN AF: 0.0208

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0191 Hom.: 45

Bravo AF: 0.0256

Asia WGS AF: 0.0450 AC: 157 AN: 3476

EpiCase AF: 0.0186

EpiControl AF: 0.0186

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
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	-	- -

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

Mar 03, 2015

- -

Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.2
DANN	Benign	0.42

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: rs2273761; hg19: chr6-135754208;