6-135497680-C-T

Variant names:

• chr6-135497680-C-T
• rs113052089
• NM_001134831.2:c.-299G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001134831.2(AHI1):​c.-299G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.035 in 163,520 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (146 hom., cov: 33)
  • Exomes 𝑓: 0.036 (10 hom.)
• Consequence: AHI1 NM_001134831.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.881

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-DT (HGNC:32526): (AHI1 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-135497680-C-T is Benign according to our data. Variant chr6-135497680-C-T is described in ClinVar as [Benign]. Clinvar id is 355514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0349 (5316/152366) while in subpopulation AMR AF= 0.0479 (733/15310). AF 95% confidence interval is 0.045. There are 146 homozygotes in gnomad4. There are 2627 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 146 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.-299G>A		5_prime_UTR_variant	Exon 1 of 29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.-299G>A		5_prime_UTR_variant	Exon 1 of 29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5317 AN: 152250 Hom.: 146 Cov.: 33

Gnomad AFR AF: 0.00902

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0479

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.0716

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0287

GnomAD4 exome AF: 0.0359 AC: 400 AN: 11154 Hom.: 10 Cov.: 0 AF XY: 0.0354 AC XY: 251 AN XY: 7084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0291

Gnomad4 FIN exome AF: 0.0476

Gnomad4 NFE exome AF: 0.0411

Gnomad4 OTH exome AF: 0.0257

GnomAD4 genome AF: 0.0349 AC: 5316 AN: 152366 Hom.: 146 Cov.: 33 AF XY: 0.0353 AC XY: 2627 AN XY: 74514

Gnomad4 AFR AF: 0.00899

Gnomad4 AMR AF: 0.0479

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0277

Gnomad4 FIN AF: 0.0716

Gnomad4 NFE AF: 0.0463

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0405 Hom.: 14

Bravo AF: 0.0339

Asia WGS AF: 0.0140 AC: 49 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Dec 30, 2019

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	-0.72
CADD	Benign	7.3
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs113052089; hg19: chr6-135818818;