Genetic Variant AHI1:p.Ser268Ser (chr6-135463252-T-G) – ACMG Classification: Benign (-21 pts)

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.804A>C(p.Ser268Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,610,956 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S268S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0099 ( 22 hom., cov: 30)

Exomes 𝑓: 0.0011 ( 17 hom. )

Consequence

AHI1
NM_001134831.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.160

Publications

3 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 (BayesDel_noAF=-0.84).

BP6

Variant 6-135463252-T-G is Benign according to our data. Variant chr6-135463252-T-G is described in ClinVar as Benign. ClinVar VariationId is 128328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.16 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00989 (1497/151384) while in subpopulation AFR AF = 0.0339 (1396/41152). AF 95% confidence interval is 0.0324. There are 22 homozygotes in GnomAd4. There are 696 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 22 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134831.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AHI1	NM_001134831.2	MANE Select	c.804A>C	p.Ser268Ser	synonymous	Exon 8 of 29	NP_001128303.1
AHI1	NM_001134830.2		c.804A>C	p.Ser268Ser	synonymous	Exon 6 of 27	NP_001128302.1
AHI1	NM_001350503.2		c.804A>C	p.Ser268Ser	synonymous	Exon 8 of 29	NP_001337432.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AHI1	ENST00000265602.11	TSL:1 MANE Select	c.804A>C	p.Ser268Ser	synonymous	Exon 8 of 29	ENSP00000265602.6
AHI1	ENST00000367800.8	TSL:1	c.804A>C	p.Ser268Ser	synonymous	Exon 6 of 27	ENSP00000356774.4
AHI1	ENST00000457866.6	TSL:1	c.804A>C	p.Ser268Ser	synonymous	Exon 7 of 28	ENSP00000388650.2

Frequencies

GnomAD3 genomes

AF:

0.00987

AC:

1493

AN:

151266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00495

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00578

GnomAD2 exomes

AF:

0.00259

AC:

642

AN:

247712

AF XY:

0.00195

show subpopulations

Gnomad AFR exome

AF:

0.0344

Gnomad AMR exome

AF:

0.00227

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000187

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00109

AC:

1591

AN:

1459572

Hom.:

Cov.:

AF XY:

0.000941

AC XY:

683

AN XY:

726066

show subpopulations

African (AFR)

AF:

0.0352

AC:

1179

AN:

33450

American (AMR)

AF:

0.00257

AC:

115

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.000186

AC:

AN:

86044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52122

Middle Eastern (MID)

AF:

0.00370

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000792

AC:

AN:

1111518

Other (OTH)

AF:

0.00285

AC:

172

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

158

236

315

394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00989

AC:

1497

AN:

151384

Hom.:

Cov.:

AF XY:

0.00942

AC XY:

696

AN XY:

73904

show subpopulations

African (AFR)

AF:

0.0339

AC:

1396

AN:

41152

American (AMR)

AF:

0.00494

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000210

AC:

AN:

4756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10442

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67910

Other (OTH)

AF:

0.00572

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00319

Hom.:

Bravo

AF:

0.0118

Asia WGS

AF:

0.00289

AC:

AN:

3476

EpiCase

AF:

0.000329

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 09, 2015

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.

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Joubert syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joubert syndrome 3

Benign:1

Jan 12, 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.8

(source)

DANN

Benign

0.61

PhyloP100

-0.16

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over