rs13218824

chr6-135428544-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001134831.2(AHI1):c.2623+85A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,373,918 control chromosomes in the GnomAD database, including 1,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (75 hom., cov: 32)
  • Exomes 𝑓: 0.038 (978 hom.)
• Consequence: AHI1 NM_001134831.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.586

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-135428544-T-C is Benign according to our data. Variant chr6-135428544-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 675205.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0271 (4116/151684) while in subpopulation NFE AF= 0.0407 (2748/67574). AF 95% confidence interval is 0.0394. There are 75 homozygotes in gnomad4. There are 2016 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 75 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.2623+85A>G		intron_variant		ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.2623+85A>G		intron_variant		1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4118 AN: 151566 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00785

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0465

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.0216

GnomAD4 exome AF: 0.0375 AC: 45879 AN: 1222234 Hom.: 978 AF XY: 0.0373 AC XY: 22038 AN XY: 591520

Gnomad4 AFR exome AF: 0.00477

Gnomad4 AMR exome AF: 0.0181

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.0000597

Gnomad4 SAS exome AF: 0.00804

Gnomad4 FIN exome AF: 0.0430

Gnomad4 NFE exome AF: 0.0418

Gnomad4 OTH exome AF: 0.0323

GnomAD4 genome AF: 0.0271 AC: 4116 AN: 151684 Hom.: 75 Cov.: 32 AF XY: 0.0272 AC XY: 2016 AN XY: 74168

Gnomad4 AFR AF: 0.00783

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0211

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.0465

Gnomad4 NFE AF: 0.0407

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0313 Hom.: 17

Bravo AF: 0.0252

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.4
Dann	Benign	0.79

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: rs13218824; hg19: chr6-135749682;