6-135394870-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0700

Publications

8 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Joubert syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Ambry Genetics
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with ocular defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

AHI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.006).

BP6

Variant 6-135394870-T-C is Benign according to our data. Variant chr6-135394870-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHI1	NM_001134831.2 link	c.3015A>G	p.Ser1005Ser	synonymous_variant	Exon 23 of 29	ENST00000265602.11	NP_001128303.1	Q8N157-1Q8NER0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHI1	ENST00000265602.11 link	c.3015A>G	p.Ser1005Ser	synonymous_variant	Exon 23 of 29	1	NM_001134831.2	ENSP00000265602.6		Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2541

AN:

151948

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0179

AC:

4110

AN:

229550

AF XY:

0.0186

show subpopulations

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 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.:

AF XY:

0.0226

AC XY:

16255

AN XY:

719420

show subpopulations

African (AFR)

AF:

0.00396

AC:

132

AN:

33324

American (AMR)

AF:

0.0146

AC:

628

AN:

43014

Ashkenazi Jewish (ASJ)

AF:

0.0415

AC:

1072

AN:

25830

East Asian (EAS)

AF:

0.00

AC:

AN:

39444

South Asian (SAS)

AF:

0.00950

AC:

799

AN:

84064

European-Finnish (FIN)

AF:

0.00857

AC:

453

AN:

52846

Middle Eastern (MID)

AF:

0.0237

AC:

136

AN:

5742

European-Non Finnish (NFE)

AF:

0.0256

AC:

28290

AN:

1104976

Other (OTH)

AF:

0.0222

AC:

1331

AN:

59950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1482

2963

4445

5926

7408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1042

2084

3126

4168

5210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0167

AC:

2538

AN:

152066

Hom.:

Cov.:

AF XY:

0.0158

AC XY:

1171

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00433

AC:

180

AN:

41524

American (AMR)

AF:

0.0166

AC:

253

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0413

AC:

143

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00767

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00575

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0256

AC:

1736

AN:

67884

Other (OTH)

AF:

0.0270

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

124

248

373

497

621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0221

Hom.:

Bravo

AF:

0.0170

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Joubert syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.1

(source)

DANN

Benign

0.69

PhyloP100

-0.070

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over