rs4759021

Variant names:

• chr12-53321084-G-A
• rs4759021
• NM_015665.6:c.123+259C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015665.6(AAAS):​c.123+259C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 588,648 control chromosomes in the GnomAD database, including 22,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4911 hom., cov: 31)
  • Exomes 𝑓: 0.27 (18055 hom.)
• Consequence: AAAS NM_015665.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.420
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 12-53321084-G-A is Benign according to our data. Variant chr12-53321084-G-A is described in ClinVar as Benign. ClinVar VariationId is 1263974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

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.123+259C>T		intron	N/A	NP_056480.1	Q9NRG9-1
	AAAS	NM_001173466.2		c.123+259C>T		intron	N/A	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.123+259C>T		intron	N/A	ENSP00000209873.4	Q9NRG9-1
	AAAS	ENST00000394384.7	TSL:1	c.123+259C>T		intron	N/A	ENSP00000377908.3	Q9NRG9-2
	AAAS	ENST00000547757.2	TSL:2	c.-1121C>T		5_prime_UTR	Exon 1 of 12	ENSP00000448020.2	F8VUB6

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33371 AN: 151830 Hom.: 4912 Cov.: 31

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.0927

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.265 AC: 115791 AN: 436700 Hom.: 18055 Cov.: 5 AF XY: 0.258 AC XY: 58961 AN XY: 228644

African (AFR) AF: 0.0525 AC: 639 AN: 12170

American (AMR) AF: 0.185 AC: 3097 AN: 16778

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 3597 AN: 12648

East Asian (EAS) AF: 0.000791 AC: 22 AN: 27804

South Asian (SAS) AF: 0.114 AC: 4960 AN: 43394

European-Finnish (FIN) AF: 0.318 AC: 8222 AN: 25868

Middle Eastern (MID) AF: 0.242 AC: 447 AN: 1844

European-Non Finnish (NFE) AF: 0.325 AC: 88422 AN: 271820

Other (OTH) AF: 0.262 AC: 6385 AN: 24374

GnomAD4 genome AF: 0.220 AC: 33361 AN: 151948 Hom.: 4911 Cov.: 31 AF XY: 0.216 AC XY: 16046 AN XY: 74240

African (AFR) AF: 0.0540 AC: 2241 AN: 41462

American (AMR) AF: 0.210 AC: 3209 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1032 AN: 3468

East Asian (EAS) AF: 0.00387 AC: 20 AN: 5172

South Asian (SAS) AF: 0.0932 AC: 448 AN: 4808

European-Finnish (FIN) AF: 0.315 AC: 3310 AN: 10522

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.326 AC: 22162 AN: 67936

Other (OTH) AF: 0.257 AC: 542 AN: 2112

Alfa AF: 0.291 Hom.: 3593

Bravo AF: 0.207

Asia WGS AF: 0.0620 AC: 220 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.3
DANN	Benign	0.73
PhyloP100		0.42
PromoterAI		0.0072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4759021; hg19: chr12-53714868;