rs138994144

Variant names:

• chr12-53307457-G-A
• rs138994144
• ENST00000548931.6:c.*33C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000552876.5(AAAS):​n.2016C>T variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,574,330 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (44 hom.)
• Consequence: AAAS ENST00000552876.5 splice_region, non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.552

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-53307457-G-A is Benign according to our data. Variant chr12-53307457-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 309717.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00333 (508/152332) while in subpopulation SAS AF = 0.0319 (154/4828). AF 95% confidence interval is 0.0278. There are 7 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AAAS	NM_015665.6	c.*32C>T		downstream_gene_variant		ENST00000209873.9	NP_056480.1
AAAS	NM_001173466.2	c.*32C>T		downstream_gene_variant			NP_001166937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9	c.*32C>T		downstream_gene_variant		1	NM_015665.6	ENSP00000209873.4

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 503 AN: 152214 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00794

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0321

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00422 AC: 896 AN: 212488 AF XY: 0.00513

Gnomad AFR exome AF: 0.00922

Gnomad AMR exome AF: 0.000105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000450

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000433

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00175 AC: 2483 AN: 1421998 Hom.: 44 Cov.: 33 AF XY: 0.00238 AC XY: 1681 AN XY: 706768

African (AFR) AF: 0.00751 AC: 246 AN: 32770

American (AMR) AF: 0.000128 AC: 5 AN: 39020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25586

East Asian (EAS) AF: 0.000205 AC: 8 AN: 38936

South Asian (SAS) AF: 0.0241 AC: 2021 AN: 83774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52408

Middle Eastern (MID) AF: 0.00496 AC: 27 AN: 5442

European-Non Finnish (NFE) AF: 0.00000922 AC: 10 AN: 1085020

Other (OTH) AF: 0.00281 AC: 166 AN: 59042

GnomAD4 genome AF: 0.00333 AC: 508 AN: 152332 Hom.: 7 Cov.: 33 AF XY: 0.00383 AC XY: 285 AN XY: 74488

African (AFR) AF: 0.00806 AC: 335 AN: 41580

American (AMR) AF: 0.000784 AC: 12 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0319 AC: 154 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.00275

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glucocorticoid deficiency with achalasia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.4
DANN	Benign	0.45
PhyloP100		0.55
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

Publications

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Other links and lift over

dbSNP: rs138994144; hg19: chr12-53701241;