12-53321084-G-A

Position:

• chr12-53321084-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AAAS	NM_015665.6	c.123+259C>T		intron_variant		ENST00000209873.9	NP_056480.1
AAAS	NM_001173466.2	c.123+259C>T		intron_variant			NP_001166937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9	c.123+259C>T		intron_variant		1	NM_015665.6	ENSP00000209873	P1

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

Gnomad4 AFR exome AF: 0.0525

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.284

Gnomad4 EAS exome AF: 0.000791

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.318

Gnomad4 NFE exome AF: 0.325

Gnomad4 OTH exome AF: 0.262

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

Gnomad4 AFR AF: 0.0540

Gnomad4 AMR AF: 0.210

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.00387

Gnomad4 SAS AF: 0.0932

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.326

Gnomad4 OTH AF: 0.257

Alfa AF: 0.288 Hom.: 3202

Bravo AF: 0.207

Asia WGS AF: 0.0620 AC: 220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.3
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs4759021; hg19: chr12-53714868;