12-53309020-TCG-CCC

Variant names:

• chr12-53309020-TCT-CCC
• NM_015665.6:c.936-2_936delAGAinsGGG
• AAAS p.313

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_015665.6(AAAS):​c.936-2_936delAGAinsGGG​(p.313) variant causes a splice acceptor, splice region, synonymous, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AAAS NM_015665.6 splice_acceptor, splice_region, synonymous, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.84
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4, offset of 50, new splice context is: gaggtggcctactctatcAGggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

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.936-2_936delAGAinsGGG	p.313	splice_acceptor splice_region synonymous intron	N/A	NP_056480.1	Q9NRG9-1
	AAAS	NM_001173466.2		c.837-2_837delAGAinsGGG	p.280	splice_acceptor splice_region synonymous 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.936-2_936delAGAinsGGG	p.313	splice_acceptor splice_region synonymous intron	N/A	ENSP00000209873.4	Q9NRG9-1
	AAAS	ENST00000394384.7	TSL:1	c.837-2_837delAGAinsGGG	p.280	splice_acceptor splice_region synonymous intron	N/A	ENSP00000377908.3	Q9NRG9-2
	AAAS	ENST00000547757.2	TSL:2	c.-16-2_-16delAGAinsGGG		splice_region	Exon 8 of 12	ENSP00000448020.2	F8VUB6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-53702804;