6-135285617-C-G

Variant names:

• chr6-135285617-C-G
• rs9494209
• NM_001134831.2:c.*28G>C

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.*28G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,602,404 control chromosomes in the GnomAD database, including 6,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1583 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4640 hom.)
• Consequence: AHI1 NM_001134831.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.575
• Publications: 8 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=-0.88).
• BP6: Variant 6-135285617-C-G is Benign according to our data. Variant chr6-135285617-C-G is described in ClinVar as Benign. ClinVar VariationId is 260835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.*28G>C		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.*28G>C		3_prime_UTR_variant	Exon 29 of 29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17652 AN: 152076 Hom.: 1572 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0844

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.0673

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0243

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0666

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.0730 AC: 17639 AN: 241654 AF XY: 0.0711

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.0688

Gnomad ASJ exome AF: 0.0268

Gnomad EAS exome AF: 0.0610

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0614

Gnomad OTH exome AF: 0.0622

GnomAD4 exome AF: 0.0708 AC: 102717 AN: 1450210 Hom.: 4640 Cov.: 29 AF XY: 0.0707 AC XY: 51028 AN XY: 721362

African (AFR) AF: 0.257 AC: 8475 AN: 32982

American (AMR) AF: 0.0715 AC: 3154 AN: 44112

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 744 AN: 26034

East Asian (EAS) AF: 0.0807 AC: 3187 AN: 39508

South Asian (SAS) AF: 0.0986 AC: 8397 AN: 85164

European-Finnish (FIN) AF: 0.0281 AC: 1478 AN: 52542

Middle Eastern (MID) AF: 0.0659 AC: 378 AN: 5736

European-Non Finnish (NFE) AF: 0.0654 AC: 72261 AN: 1104202

Other (OTH) AF: 0.0775 AC: 4643 AN: 59930

GnomAD4 genome AF: 0.116 AC: 17703 AN: 152194 Hom.: 1583 Cov.: 32 AF XY: 0.112 AC XY: 8331 AN XY: 74422

African (AFR) AF: 0.250 AC: 10375 AN: 41496

American (AMR) AF: 0.0841 AC: 1286 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3470

East Asian (EAS) AF: 0.0673 AC: 349 AN: 5186

South Asian (SAS) AF: 0.108 AC: 519 AN: 4826

European-Finnish (FIN) AF: 0.0243 AC: 258 AN: 10610

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0666 AC: 4532 AN: 68006

Other (OTH) AF: 0.110 AC: 233 AN: 2110

Alfa AF: 0.0385 Hom.: 43

Bravo AF: 0.125

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 3 Benign:1

Jan 13, 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 16, 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	-0.88
CADD	Benign	6.8
DANN	Benign	0.59
PhyloP100		0.57
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: rs9494209; hg19: chr6-135606755; COSMIC: COSV55624645;