Genetic Variant AHI1:c.-293G>T (chr6-135497759-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000457866.6(AHI1):c.-293G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 199,288 control chromosomes in the GnomAD database, including 11,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7142 hom., cov: 33)

Exomes 𝑓: 0.40 ( 3920 hom. )

Consequence

AHI1
ENST00000457866.6 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.45

Publications

27 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 links:

AHI1-DT (HGNC:32526): (AHI1 divergent transcript)

AHI1-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 6-135497759-C-A is Benign according to our data. Variant chr6-135497759-C-A is described in ClinVar as Benign. ClinVar VariationId is 355518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000457866.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AHI1	NM_001134831.2	MANE Select	c.-378G>T	upstream_gene	N/A	NP_001128303.1	Q8N157-1
AHI1	NM_001134830.2		c.-231G>T	upstream_gene	N/A	NP_001128302.1	Q8N157-1
AHI1	NM_001350503.2		c.-487G>T	upstream_gene	N/A	NP_001337432.1	Q8N157-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AHI1	ENST00000457866.6	TSL:1	c.-293G>T	5_prime_UTR	Exon 1 of 28	ENSP00000388650.2	Q8N157-1
AHI1	ENST00000681022.1		c.-2275G>T	5_prime_UTR	Exon 1 of 27	ENSP00000505121.1	Q8N157-1
AHI1	ENST00000681340.1		c.-464G>T	5_prime_UTR	Exon 1 of 29	ENSP00000505666.1	Q8N157-1

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45583

AN:

152066

Hom.:

7135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.201

Gnomad AMI

AF:

0.284

Gnomad AMR

AF:

0.297

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.319

Gnomad SAS

AF:

0.416

Gnomad FIN

AF:

0.292

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.349

Gnomad OTH

AF:

0.307

GnomAD2 exomes

AF:

0.397

AC:

282

AN:

710

AF XY:

0.426

show subpopulations

Gnomad AFR exome

AF:

0.167

Gnomad AMR exome

AF:

0.307

Gnomad ASJ exome

AF:

0.450

Gnomad EAS exome

AF:

0.357

Gnomad FIN exome

AF:

0.550

Gnomad NFE exome

AF:

0.412

Gnomad OTH exome

AF:

0.269

GnomAD4 exome

AF:

0.399

AC:

18801

AN:

47106

Hom.:

3920

Cov.:

AF XY:

0.406

AC XY:

11816

AN XY:

29084

show subpopulations

African (AFR)

AF:

0.264

AC:

AN:

254

American (AMR)

AF:

0.268

AC:

AN:

328

Ashkenazi Jewish (ASJ)

AF:

0.407

AC:

390

AN:

958

East Asian (EAS)

AF:

0.298

AC:

AN:

124

South Asian (SAS)

AF:

0.438

AC:

7207

AN:

16470

European-Finnish (FIN)

AF:

0.368

AC:

1303

AN:

3544

Middle Eastern (MID)

AF:

0.387

AC:

AN:

124

European-Non Finnish (NFE)

AF:

0.380

AC:

8964

AN:

23582

Other (OTH)

AF:

0.405

AC:

697

AN:

1722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

474

949

1423

1898

2372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.300

AC:

45615

AN:

152182

Hom.:

7142

Cov.:

AF XY:

0.299

AC XY:

22234

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.201

AC:

8361

AN:

41556

American (AMR)

AF:

0.297

AC:

4549

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

1263

AN:

3470

East Asian (EAS)

AF:

0.318

AC:

1644

AN:

5162

South Asian (SAS)

AF:

0.416

AC:

2009

AN:

4828

European-Finnish (FIN)

AF:

0.292

AC:

3094

AN:

10588

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.349

AC:

23705

AN:

67962

Other (OTH)

AF:

0.310

AC:

655

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1703

3406

5110

6813

8516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.271

Hom.:

1434

Bravo

AF:

0.293

Asia WGS

AF:

0.317

AC:

1103

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Joubert syndrome 3 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

1.4

PromoterAI

-0.20

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over