rs397885237

Variant names:

• chr6-135285247-C-CCA
• rs397885237
• NM_001134831.2:c.*396_*397dupTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001134831.2(AHI1):​c.*396_*397dupTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0935 in 233,098 control chromosomes in the GnomAD database, including 1,712 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1578 hom., cov: 31)
  • Exomes 𝑓: 0.051 (134 hom.)
• Consequence: AHI1 NM_001134831.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.592
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 6-135285247-C-CCA is Benign according to our data. Variant chr6-135285247-C-CCA is described in ClinVar as [Likely_benign]. Clinvar id is 355489.Status of the report is criteria_provided_single_submitter, 1 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.*396_*397dupTG		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.*396_*397dupTG		3_prime_UTR_variant	Exon 29 of 29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17642 AN: 152092 Hom.: 1567 Cov.: 31

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0845

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.0673

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0243

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0666

Gnomad OTH AF: 0.104

GnomAD4 exome AF: 0.0507 AC: 4102 AN: 80888 Hom.: 134 Cov.: 0 AF XY: 0.0513 AC XY: 2172 AN XY: 42334

African (AFR) AF: 0.159 AC: 320 AN: 2012

American (AMR) AF: 0.0646 AC: 275 AN: 4260

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 45 AN: 2232

East Asian (EAS) AF: 0.0472 AC: 229 AN: 4850

South Asian (SAS) AF: 0.0678 AC: 646 AN: 9522

European-Finnish (FIN) AF: 0.0207 AC: 74 AN: 3574

Middle Eastern (MID) AF: 0.0348 AC: 11 AN: 316

European-Non Finnish (NFE) AF: 0.0459 AC: 2274 AN: 49544

Other (OTH) AF: 0.0498 AC: 228 AN: 4578

GnomAD4 genome AF: 0.116 AC: 17693 AN: 152210 Hom.: 1578 Cov.: 31 AF XY: 0.112 AC XY: 8322 AN XY: 74420

African (AFR) AF: 0.250 AC: 10363 AN: 41478

American (AMR) AF: 0.0842 AC: 1288 AN: 15290

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

East Asian (EAS) AF: 0.0672 AC: 349 AN: 5190

South Asian (SAS) AF: 0.108 AC: 523 AN: 4832

European-Finnish (FIN) AF: 0.0243 AC: 258 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0666 AC: 4528 AN: 68020

Other (OTH) AF: 0.110 AC: 233 AN: 2112

Alfa AF: 0.0923 Hom.: 107

Bravo AF: 0.125

Asia WGS AF: 0.145 AC: 505 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397885237; hg19: chr6-135606385;