rs1052502

Variant names:

• chr6-135285427-G-A
• rs1052502
• NM_001134831.2:c.*218C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001134831.2(AHI1):​c.*218C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 595,260 control chromosomes in the GnomAD database, including 16,330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (11555 hom., cov: 32)
  • Exomes 𝑓: 0.095 (4775 hom.)
• Consequence: AHI1 NM_001134831.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.113
• Publications: 14 publications found

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]

AHI1 Gene-Disease associations (from GenCC):

• Joubert syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with ocular defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ENSG00000234084 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-135285427-G-A is Benign according to our data. Variant chr6-135285427-G-A is described in ClinVar as [Benign]. Clinvar id is 355491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.*218C>T		3_prime_UTR_variant	Exon 29 of 29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.*218C>T		3_prime_UTR_variant	Exon 29 of 29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39462 AN: 152024 Hom.: 11505 Cov.: 32

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0735

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.0946 AC: 41915 AN: 443118 Hom.: 4775 Cov.: 4 AF XY: 0.0914 AC XY: 21467 AN XY: 234942

African (AFR) AF: 0.717 AC: 8689 AN: 12112

American (AMR) AF: 0.112 AC: 2091 AN: 18648

Ashkenazi Jewish (ASJ) AF: 0.0563 AC: 780 AN: 13856

East Asian (EAS) AF: 0.117 AC: 3592 AN: 30664

South Asian (SAS) AF: 0.0960 AC: 4129 AN: 42992

European-Finnish (FIN) AF: 0.0296 AC: 889 AN: 29986

Middle Eastern (MID) AF: 0.0956 AC: 215 AN: 2250

European-Non Finnish (NFE) AF: 0.0688 AC: 18385 AN: 267054

Other (OTH) AF: 0.123 AC: 3145 AN: 25556

GnomAD4 genome AF: 0.260 AC: 39573 AN: 152142 Hom.: 11555 Cov.: 32 AF XY: 0.252 AC XY: 18725 AN XY: 74392

African (AFR) AF: 0.725 AC: 30088 AN: 41484

American (AMR) AF: 0.149 AC: 2272 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3470

East Asian (EAS) AF: 0.120 AC: 621 AN: 5186

South Asian (SAS) AF: 0.113 AC: 546 AN: 4824

European-Finnish (FIN) AF: 0.0252 AC: 267 AN: 10602

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0735 AC: 4998 AN: 67980

Other (OTH) AF: 0.238 AC: 501 AN: 2108

Alfa AF: 0.135 Hom.: 11875

Bravo AF: 0.291

Asia WGS AF: 0.199 AC: 694 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.91
DANN	Benign	0.60
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1052502; hg19: chr6-135606565; COSMIC: COSV55634852;