NM_015665.6:c.1566C>T

Variant names:

• chr12-53307564-G-A
• rs886049648
• NM_015665.6:c.1566C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_015665.6(AAAS):​c.1566C>T​(p.Ser522Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: AAAS NM_015665.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.888
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1250267).
• BP6: Variant 12-53307564-G-A is Benign according to our data. Variant chr12-53307564-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 309720.
• BP7: Synonymous conserved (PhyloP=0.888 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AAAS	NM_015665.6	MANE Select	c.1566C>T	p.Ser522Ser	synonymous	Exon 16 of 16	NP_056480.1	Q9NRG9-1
	AAAS	NM_001173466.2		c.1467C>T	p.Ser489Ser	synonymous	Exon 15 of 15	NP_001166937.1	Q9NRG9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AAAS	ENST00000209873.9	TSL:1 MANE Select	c.1566C>T	p.Ser522Ser	synonymous	Exon 16 of 16	ENSP00000209873.4	Q9NRG9-1
	AAAS	ENST00000394384.7	TSL:1	c.1467C>T	p.Ser489Ser	synonymous	Exon 15 of 15	ENSP00000377908.3	Q9NRG9-2
	AAAS	ENST00000548931.6	TSL:5	c.1001C>T	p.Pro334Leu	missense	Exon 10 of 10	ENSP00000457518.1	H3BU82

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461860 Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111996

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	3.2
DANN	Benign	0.95
DEOGEN2	Benign	0.0057	T
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.13	T
PhyloP100		0.89
PROVEAN	Benign	1.3	N
Sift	Benign	0.049	D
MVP		0.84
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs886049648; hg19: chr12-53701348;