rs41288017

chr6-135428747-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001134831.2(AHI1):c.2505G>A(p.Arg835=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,602,692 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (26 hom.)
• Consequence: AHI1 NM_001134831.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.54

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 6-135428747-C-T is Benign according to our data. Variant chr6-135428747-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135428747-C-T is described in Lovd as [Benign]. Variant chr6-135428747-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.54 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.2505G>A	p.Arg835=	synonymous_variant	19/29	ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.2505G>A	p.Arg835=	synonymous_variant	19/29	1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 575 AN: 151726 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00526

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00623

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00385 AC: 907 AN: 235472 Hom.: 1 AF XY: 0.00405 AC XY: 516 AN XY: 127380

Gnomad AFR exome AF: 0.000753

Gnomad AMR exome AF: 0.00422

Gnomad ASJ exome AF: 0.00155

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.00633

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00481 AC: 6977 AN: 1450848 Hom.: 26 Cov.: 30 AF XY: 0.00490 AC XY: 3532 AN XY: 720906

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00504

Gnomad4 ASJ exome AF: 0.00166

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00164

Gnomad4 FIN exome AF: 0.000303

Gnomad4 NFE exome AF: 0.00562

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.00379 AC: 575 AN: 151844 Hom.: 1 Cov.: 32 AF XY: 0.00368 AC XY: 273 AN XY: 74248

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00525

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00622

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00495 Hom.: 1

Bravo AF: 0.00420

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2015	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	AHI1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2019	This variant is associated with the following publications: (PMID: 18782849, 16453322) -

Joubert syndrome 3 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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	-0.28
Cadd	Benign	7.5
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41288017; hg19: chr6-135749885;