rs6940875

chr6-135394832-T-G

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.3053A>C(p.Gln1018Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,608,110 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1018R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (79 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (69 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.67

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=0.0038753152).
• BP6: Variant 6-135394832-T-G is Benign according to our data. Variant chr6-135394832-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 128327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135394832-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.3053A>C	p.Gln1018Pro	missense_variant	23/29	ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.3053A>C	p.Gln1018Pro	missense_variant	23/29	1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2385 AN: 152062 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.0550

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00405 AC: 973 AN: 240244 Hom.: 29 AF XY: 0.00285 AC XY: 370 AN XY: 129986

Gnomad AFR exome AF: 0.0577

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000711

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000138

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.00239

GnomAD4 exome AF: 0.00171 AC: 2491 AN: 1455930 Hom.: 69 Cov.: 30 AF XY: 0.00150 AC XY: 1087 AN XY: 723642

Gnomad4 AFR exome AF: 0.0584

Gnomad4 AMR exome AF: 0.00223

Gnomad4 ASJ exome AF: 0.000655

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000941

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.00307

GnomAD4 genome AF: 0.0157 AC: 2388 AN: 152180 Hom.: 79 Cov.: 32 AF XY: 0.0149 AC XY: 1106 AN XY: 74420

Gnomad4 AFR AF: 0.0549

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00311 Hom.: 25

Bravo AF: 0.0173

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0651 AC: 244

ESP6500EA AF: 0.000364 AC: 3

ExAC AF: 0.00476 AC: 575

Asia WGS AF: 0.00376 AC: 13 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 19, 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
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T;T;.
Eigen	Benign	0.024
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.71	D
MetaRNN	Benign	0.0039	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.56	N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.048	D;D;D;D
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.98	D;D;D;D
Vest4		0.26
MVP		0.42
MPC		0.19
ClinPred		0.025	T
GERP RS		4.3
Varity_R		0.11
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6940875; hg19: chr6-135715970; COSMIC: COSV99039550;