6-135404993-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001134831.2(AHI1):c.2962-16A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00975 in 1,593,840 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (5 hom., cov: 32)
  • Exomes 𝑓: 0.010 (93 hom.)
• Consequence: AHI1 NM_001134831.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.435

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 6-135404993-T-C is Benign according to our data. Variant chr6-135404993-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 260852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHI1	NM_001134831.2	c.2962-16A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000265602.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHI1	ENST00000265602.11	c.2962-16A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001134831.2	P2

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1066 AN: 152174 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00676 AC: 1657 AN: 245052 Hom.: 9 AF XY: 0.00679 AC XY: 903 AN XY: 133040

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.000303

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000369

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.00983

Gnomad OTH exome AF: 0.00787

GnomAD4 exome AF: 0.0100 AC: 14466 AN: 1441548 Hom.: 93 Cov.: 27 AF XY: 0.00985 AC XY: 7073 AN XY: 718166

Gnomad4 AFR exome AF: 0.00142

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.000193

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000457

Gnomad4 FIN exome AF: 0.0143

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00699

GnomAD4 genome AF: 0.00700 AC: 1066 AN: 152292 Hom.: 5 Cov.: 32 AF XY: 0.00720 AC XY: 536 AN XY: 74458

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00336 Hom.: 0

Bravo AF: 0.00595

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

AHI1: BS1, BS2 -

Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	5.0
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs41287056; hg19: chr6-135726131;