rs41287054

Variant names:

• chr6-135394870-T-C
• rs41287054
• NM_001134831.2:c.3015A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001134831.2(AHI1):​c.3015A>G​(p.Ser1005Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,601,256 control chromosomes in the GnomAD database, including 479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (29 hom., cov: 32)
  • Exomes 𝑓: 0.023 (450 hom.)
• Consequence: AHI1 NM_001134831.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0700

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-135394870-T-C is Benign according to our data. Variant chr6-135394870-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135394870-T-C is described in Lovd as [Benign]. Variant chr6-135394870-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2538/152066) while in subpopulation NFE AF= 0.0256 (1736/67884). AF 95% confidence interval is 0.0246. There are 29 homozygotes in gnomad4. There are 1171 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2	c.3015A>G	p.Ser1005Ser	synonymous_variant	Exon 23 of 29	ENST00000265602.11	NP_001128303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11	c.3015A>G	p.Ser1005Ser	synonymous_variant	Exon 23 of 29	1	NM_001134831.2	ENSP00000265602.6

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2541 AN: 151948 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.0617

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0413

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.00575

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0278

GnomAD3 exomes AF: 0.0179 AC: 4110 AN: 229550 Hom.: 44 AF XY: 0.0186 AC XY: 2307 AN XY: 123750

Gnomad AFR exome AF: 0.00410

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0400

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00926

Gnomad FIN exome AF: 0.00804

Gnomad NFE exome AF: 0.0261

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0227 AC: 32841 AN: 1449190 Hom.: 450 Cov.: 31 AF XY: 0.0226 AC XY: 16255 AN XY: 719420

Gnomad4 AFR exome AF: 0.00396

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.0415

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00950

Gnomad4 FIN exome AF: 0.00857

Gnomad4 NFE exome AF: 0.0256

Gnomad4 OTH exome AF: 0.0222

GnomAD4 genome AF: 0.0167 AC: 2538 AN: 152066 Hom.: 29 Cov.: 32 AF XY: 0.0158 AC XY: 1171 AN XY: 74342

Gnomad4 AFR AF: 0.00433

Gnomad4 AMR AF: 0.0166

Gnomad4 ASJ AF: 0.0413

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.00575

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0237 Hom.: 32

Bravo AF: 0.0170

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 07, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 03, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 3 Benign:2

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. -

Nov 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial aplasia of the vermis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.78
CADD	Benign	6.1
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs41287054; hg19: chr6-135716008;