12-53307457-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000548931.6(AAAS):c.*33C>T variant causes a 3 prime UTR 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. 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 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.552

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]

ACMG classification

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 GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAAS	NM_015665.6			downstream_gene_variant		ENST00000209873.9
AAAS	NM_001173466.2			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAAS	ENST00000209873.9			downstream_gene_variant		1	NM_015665.6	P1

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 503 AN: 152214 Hom.: 7 Cov.: 33

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.: 16 AF XY: 0.00513 AC XY: 588 AN XY: 114692

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.: 44 Cov.: 33 AF XY: 0.00238 AC XY: 1681 AN XY: 706768

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.: 7 Cov.: 33 AF XY: 0.00383 AC XY: 285 AN XY: 74488

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.: 0

Bravo AF: 0.00275

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glucocorticoid deficiency with achalasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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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

Other links and lift over

dbSNP: rs138994144; hg19: chr12-53701241;