rs80027466

Variant names:

• chr12-53314308-A-G
• rs80027466
• NM_015665.6:c.679T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• triple-A syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128251.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015665.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AAAS	NM_015665.6	MANE Select	c.679T>C	p.Leu227Leu	synonymous	Exon 7 of 16	NP_056480.1
	AAAS	NM_001173466.2		c.580T>C	p.Leu194Leu	synonymous	Exon 6 of 15	NP_001166937.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AAAS	ENST00000209873.9	TSL:1 MANE Select	c.679T>C	p.Leu227Leu	synonymous	Exon 7 of 16	ENSP00000209873.4
	AAAS	ENST00000394384.7	TSL:1	c.580T>C	p.Leu194Leu	synonymous	Exon 6 of 15	ENSP00000377908.3
	AAAS	ENST00000547757.2	TSL:2	c.-273T>C		5_prime_UTR_premature_start_codon_gain	Exon 5 of 12	ENSP00000448020.2

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

GnomAD2 exomes AF: 0.00482 AC: 1211 AN: 251406 AF XY: 0.00545

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 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

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00212 AC: 95 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0112 AC: 965 AN: 86258

European-Finnish (FIN) AF: 0.00208 AC: 111 AN: 53412

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.00602 AC: 6699 AN: 1112002

Other (OTH) AF: 0.00536 AC: 324 AN: 60396

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

African (AFR) AF: 0.00106 AC: 44 AN: 41570

American (AMR) AF: 0.00164 AC: 25 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00996 AC: 48 AN: 4820

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00666 AC: 453 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00459 Hom.: 1

Bravo AF: 0.00390

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00664

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	Glucocorticoid deficiency with achalasia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.6
DANN	Benign	0.90
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs80027466; hg19: chr12-53708092;