rs146416468

chr6-135466046-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001134831.2(AHI1):c.517G>A(p.Ala173Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,613,882 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (17 hom.)
• Consequence: AHI1 NM_001134831.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.154

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002779305).
• BP6: Variant 6-135466046-C-T is Benign according to our data. Variant chr6-135466046-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 166664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135466046-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.517G>A	p.Ala173Thr	missense_variant	7/29	ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.517G>A	p.Ala173Thr	missense_variant	7/29	1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 512 AN: 152122 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00405 AC: 1010 AN: 249150 Hom.: 5 AF XY: 0.00430 AC XY: 581 AN XY: 135168

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00611

GnomAD4 exome AF: 0.00293 AC: 4288 AN: 1461642 Hom.: 17 Cov.: 31 AF XY: 0.00309 AC XY: 2248 AN XY: 727092

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.0172

Gnomad4 NFE exome AF: 0.00255

Gnomad4 OTH exome AF: 0.00345

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152240 Hom.: 1 Cov.: 32 AF XY: 0.00390 AC XY: 290 AN XY: 74434

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0175

Gnomad4 NFE AF: 0.00357

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00319 Hom.: 3

Bravo AF: 0.00225

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000517 AC: 2

ESP6500EA AF: 0.00327 AC: 27

ExAC AF: 0.00397 AC: 480

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00409

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 29, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	AHI1: BP4, BS2 -

Joubert syndrome 3 Benign:1

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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	0.067
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	2.4
Dann	Benign	0.95
DEOGEN2	Benign	0.085	T;T;T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.97	L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.39	N;N;N;N;N
REVEL	Benign	0.034
Sift	Benign	0.56	T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;.
Polyphen		0.024	B;B;B;B;.
Vest4		0.14
MVP		0.32
MPC		0.041
ClinPred		0.00056	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.053

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: rs146416468; hg19: chr6-135787184; COSMIC: COSV55631067;