Variant 12-53307457-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000548931.6(AAAS):c.*33C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,574,330 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0033 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 44 hom. )

Consequence

AAAS
ENST00000548931.6 splice_region

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.552

Variant links:

Genes affected

AAAS (HGNC:13666): (aladin WD repeat nucleoporin) The protein encoded by this gene is a member of the WD-repeat family of regulatory proteins and may be involved in normal development of the peripheral and central nervous system. The encoded protein is part of the nuclear pore complex and is anchored there by NDC1. Defects in this gene are a cause of achalasia-addisonianism-alacrima syndrome (AAAS), also called triple-A syndrome or Allgrove syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

AAAS links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 12-53307457-G-A is Benign according to our data. Variant chr12-53307457-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 309717.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00333 (508/152332) while in subpopulation SAS AF= 0.0319 (154/4828). AF 95% confidence interval is 0.0278. There are 7 homozygotes in gnomad4. There are 285 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AAAS	NM_015665.6 link	c.*32C>T		downstream_gene_variant		ENST00000209873.9	NP_056480.1	Q9NRG9-1
AAAS	NM_001173466.2 link	c.*32C>T		downstream_gene_variant			NP_001166937.1	Q9NRG9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9 link	c.*32C>T		downstream_gene_variant		1	NM_015665.6	ENSP00000209873.4		Q9NRG9-1

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

503

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00794

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0321

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00422

AC:

896

AN:

212488

Hom.:

AF XY:

0.00513

AC XY:

588

AN XY:

114692

show subpopulations

Gnomad AFR exome

AF:

0.00922

Gnomad AMR exome

AF:

0.000105

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000450

Gnomad SAS exome

AF:

0.0265

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000433

Gnomad OTH exome

AF:

0.00183

GnomAD4 exome

AF:

0.00175

AC:

2483

AN:

1421998

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

1681

AN XY:

706768

show subpopulations

Gnomad4 AFR exome

AF:

0.00751

Gnomad4 AMR exome

AF:

0.000128

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000205

Gnomad4 SAS exome

AF:

0.0241

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000922

Gnomad4 OTH exome

AF:

0.00281

GnomAD4 genome

AF:

0.00333

AC:

508

AN:

152332

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

285

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00806

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0319

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.00275

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Glucocorticoid deficiency with achalasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.4

DANN

Benign

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over