rs148000791

chr6-135323233-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.3257A>G(p.Glu1086Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,910 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (43 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: 7.67

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 (MetaRNN=0.008024454).
• BP6: Variant 6-135323233-T-C is Benign according to our data. Variant chr6-135323233-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 143152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135323233-T-C is described in Lovd as [Benign]. Variant chr6-135323233-T-C is described in Lovd as [Likely_benign]. Variant chr6-135323233-T-C is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00173 (264/152290) while in subpopulation EAS AF= 0.0401 (208/5188). AF 95% confidence interval is 0.0356. There are 2 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.3257A>G	p.Glu1086Gly	missense_variant	25/29	ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.3257A>G	p.Glu1086Gly	missense_variant	25/29	1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 265 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00377 AC: 938 AN: 249080 Hom.: 22 AF XY: 0.00349 AC XY: 472 AN XY: 135130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0451

Gnomad SAS exome AF: 0.000981

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00150 AC: 2186 AN: 1461620 Hom.: 43 Cov.: 30 AF XY: 0.00146 AC XY: 1065 AN XY: 727088

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0436

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.00159

Gnomad4 NFE exome AF: 0.000146

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0401

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00153 Hom.: 17

Bravo AF: 0.00195

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00378 AC: 457

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Joubert syndrome 3 Pathogenic:1 Benign:3

Likely pathogenic, flagged submission	clinical testing	UCLA Clinical Genomics Center, UCLA	Nov 20, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Oct 04, 2021	East Asian population allele frequency is 4.5% (rs148000791, 874/19,504 alleles, 22 homozygotes in gnomAD v2.1). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 24690944, 27491411, 29343940, 22995991, 25356976, 21228398, 18054307, 26035799, 26035800, 22425360, 28976722, 28391287, 25326637, 31938409) -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -

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
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.0080	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.86	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.42
MVP		0.60
MPC		0.31
ClinPred		0.062	T
GERP RS		6.1
Varity_R		0.69
gMVP		0.34

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: rs148000791; hg19: chr6-135644371; COSMIC: COSV55628168;