rs4896147

Positions:

• chr6-135455977-G-A

Variant summary

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

The ENST00000265602.11(AHI1):​c.1152-51C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,264,824 control chromosomes in the GnomAD database, including 470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (39 hom., cov: 32)
  • Exomes 𝑓: 0.027 (431 hom.)
• Consequence: AHI1 ENST00000265602.11 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.536

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-135455977-G-A is Benign according to our data. Variant chr6-135455977-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 675181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0204 (3107/152134) while in subpopulation SAS AF= 0.0388 (187/4816). AF 95% confidence interval is 0.0343. There are 39 homozygotes in gnomad4. There are 1494 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.1152-51C>T		intron_variant		ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.1152-51C>T		intron_variant		1	NM_001134831.2	ENSP00000265602	P2

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3106 AN: 152016 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00563

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0335

Gnomad SAS AF: 0.0382

Gnomad FIN AF: 0.00813

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0245

GnomAD4 exome AF: 0.0270 AC: 30098 AN: 1112690 Hom.: 431 AF XY: 0.0269 AC XY: 14414 AN XY: 534886

Gnomad4 AFR exome AF: 0.00434

Gnomad4 AMR exome AF: 0.0383

Gnomad4 ASJ exome AF: 0.00285

Gnomad4 EAS exome AF: 0.0337

Gnomad4 SAS exome AF: 0.0314

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.0284

Gnomad4 OTH exome AF: 0.0263

GnomAD4 genome AF: 0.0204 AC: 3107 AN: 152134 Hom.: 39 Cov.: 32 AF XY: 0.0201 AC XY: 1494 AN XY: 74378

Gnomad4 AFR AF: 0.00559

Gnomad4 AMR AF: 0.0329

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.0334

Gnomad4 SAS AF: 0.0388

Gnomad4 FIN AF: 0.00813

Gnomad4 NFE AF: 0.0270

Gnomad4 OTH AF: 0.0262

Alfa AF: 0.0229 Hom.: 4

Bravo AF: 0.0216

Asia WGS AF: 0.0570 AC: 198 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.86
CADD	Benign	1.4
DANN	Benign	0.67

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: rs4896147; hg19: chr6-135777115; COSMIC: COSV55635004;