rs1476957324

Variant names:

• chr12-53307576-A-C
• rs1476957324
• NM_015665.6:c.1554T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-53307576-A-C
• chr12-53307576-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015665.6(AAAS):​c.1554T>G​(p.Phe518Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,060 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AAAS NM_015665.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.505
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.418679).

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.1554T>G	p.Phe518Leu	missense	Exon 16 of 16	NP_056480.1	Q9NRG9-1
	AAAS	NM_001173466.2		c.1455T>G	p.Phe485Leu	missense	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.1554T>G	p.Phe518Leu	missense	Exon 16 of 16	ENSP00000209873.4	Q9NRG9-1
	AAAS	ENST00000394384.7	TSL:1	c.1455T>G	p.Phe485Leu	missense	Exon 15 of 15	ENSP00000377908.3	Q9NRG9-2
	AAAS	ENST00000548931.6	TSL:5	c.989T>G	p.Leu330*	stop_gained	Exon 10 of 10	ENSP00000457518.1	H3BU82

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251210 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461834 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 727204

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

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: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.51
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.012	D
Sift4G	Benign	0.26	T
Polyphen		0.79	P
Vest4		0.62
MutPred		0.27		Gain of catalytic residue at L515 (P = 0)
MVP		0.82
MPC		0.40
ClinPred		0.54	D
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.47
Mutation Taster		=86/14	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: rs1476957324; hg19: chr12-53701360;