rs80027466

Positions:

• chr12-53314308-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015665.6(AAAS):​c.679T>C​(p.Leu227Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00552 in 1,614,164 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (37 hom.)
• Consequence: AAAS NM_015665.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.90

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 12-53314308-A-G is Benign according to our data. Variant chr12-53314308-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128251.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=3}. Variant chr12-53314308-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00414 (630/152290) while in subpopulation SAS AF= 0.00996 (48/4820). AF 95% confidence interval is 0.00772. There are 3 homozygotes in gnomad4. There are 287 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AAAS	NM_015665.6	c.679T>C	p.Leu227Leu	synonymous_variant	7/16	ENST00000209873.9	NP_056480.1
AAAS	NM_001173466.2	c.580T>C	p.Leu194Leu	synonymous_variant	6/15		NP_001166937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9	c.679T>C	p.Leu227Leu	synonymous_variant	7/16	1	NM_015665.6	ENSP00000209873.4

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 629 AN: 152172 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00974

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00482 AC: 1211 AN: 251406 Hom.: 5 AF XY: 0.00545 AC XY: 740 AN XY: 135878

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.00627

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00566 AC: 8273 AN: 1461874 Hom.: 37 Cov.: 33 AF XY: 0.00586 AC XY: 4264 AN XY: 727236

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0112

Gnomad4 FIN exome AF: 0.00208

Gnomad4 NFE exome AF: 0.00602

Gnomad4 OTH exome AF: 0.00536

GnomAD4 genome AF: 0.00414 AC: 630 AN: 152290 Hom.: 3 Cov.: 32 AF XY: 0.00385 AC XY: 287 AN XY: 74460

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00996

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00666

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00486 Hom.: 1

Bravo AF: 0.00390

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00664

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	AAAS: BP4, BP7, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Glucocorticoid deficiency with achalasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.6
DANN	Benign	0.90

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: rs80027466; hg19: chr12-53708092;