12-53307615-A-G

Position:

• chr12-53307615-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015665.6(AAAS):​c.1515T>C​(p.Pro505=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,144 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (17 hom.)
• Consequence: AAAS NM_015665.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.79

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005439669).
• BP6: Variant 12-53307615-A-G is Benign according to our data. Variant chr12-53307615-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 309722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0079 (1203/152340) while in subpopulation AFR AF= 0.0272 (1132/41586). AF 95% confidence interval is 0.0259. There are 20 homozygotes in gnomad4. There are 564 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAAS	NM_015665.6	c.1515T>C	p.Pro505=	synonymous_variant	16/16	ENST00000209873.9
AAAS	NM_001173466.2	c.1416T>C	p.Pro472=	synonymous_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAAS	ENST00000209873.9	c.1515T>C	p.Pro505=	synonymous_variant	16/16	1	NM_015665.6	P1

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1198 AN: 152222 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

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: 0.000103

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00195 AC: 489 AN: 251124 Hom.: 6 AF XY: 0.00152 AC XY: 206 AN XY: 135844

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000800 AC: 1169 AN: 1461804 Hom.: 17 Cov.: 34 AF XY: 0.000674 AC XY: 490 AN XY: 727196

Gnomad4 AFR exome AF: 0.0271

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00790 AC: 1203 AN: 152340 Hom.: 20 Cov.: 33 AF XY: 0.00757 AC XY: 564 AN XY: 74508

Gnomad4 AFR AF: 0.0272

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00408 Hom.: 7

Bravo AF: 0.00926

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00236 AC: 286

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Glucocorticoid deficiency with achalasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	0.032
DANN	Benign	0.87
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0054	T
MutationTaster	Benign	0.98	D;D;D
PROVEAN	Benign	-0.020	N
Sift	Pathogenic	0.0	D
MVP		0.89
GERP RS		-7.6

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: rs35282133; hg19: chr12-53701399;