12-53307320-T-C

Variant names:

• chr12-53307320-T-C
• rs1545650
• NM_015665.6:c.*169A>G

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.*169A>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,122,930 control chromosomes in the GnomAD database, including 530,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (65762 hom., cov: 34)
  • Exomes 𝑓: 0.98 (464640 hom.)
• Consequence: AAAS NM_015665.6 downstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.01
• Publications: 7 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]

MYG1 (HGNC:17590): (MYG1 exonuclease) Predicted to enable nuclease activity. Predicted to be involved in nucleic acid phosphodiester bond hydrolysis. Predicted to act upstream of or within locomotory exploration behavior. Located in mitochondrion and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000288663 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-53307320-T-C is Benign according to our data. Variant chr12-53307320-T-C is described in ClinVar as Benign. ClinVar VariationId is 1264842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AAAS	NM_015665.6	c.*169A>G		downstream_gene_variant		ENST00000209873.9	NP_056480.1
MYG1	NM_021640.4	c.*171T>C		downstream_gene_variant		ENST00000267103.10	NP_067653.4
AAAS	NM_001173466.2	c.*169A>G		downstream_gene_variant			NP_001166937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9	c.*169A>G		downstream_gene_variant		1	NM_015665.6	ENSP00000209873.4
MYG1	ENST00000267103.10	c.*171T>C		downstream_gene_variant		1	NM_021640.4	ENSP00000267103.5

Frequencies

GnomAD3 genomes AF: 0.924 AC: 140681 AN: 152178 Hom.: 65725 Cov.: 34

Gnomad AFR AF: 0.773

Gnomad AMI AF: 0.987

Gnomad AMR AF: 0.969

Gnomad ASJ AF: 0.991

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.948

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.954

GnomAD4 exome AF: 0.978 AC: 949052 AN: 970634 Hom.: 464640 Cov.: 13 AF XY: 0.978 AC XY: 475413 AN XY: 486284

African (AFR) AF: 0.759 AC: 16861 AN: 22212

American (AMR) AF: 0.979 AC: 26667 AN: 27246

Ashkenazi Jewish (ASJ) AF: 0.990 AC: 18951 AN: 19136

East Asian (EAS) AF: 0.979 AC: 32832 AN: 33536

South Asian (SAS) AF: 0.952 AC: 57811 AN: 60752

European-Finnish (FIN) AF: 0.998 AC: 44616 AN: 44714

Middle Eastern (MID) AF: 0.961 AC: 2962 AN: 3082

European-Non Finnish (NFE) AF: 0.986 AC: 706588 AN: 716736

Other (OTH) AF: 0.966 AC: 41764 AN: 43220

GnomAD4 genome AF: 0.924 AC: 140774 AN: 152296 Hom.: 65762 Cov.: 34 AF XY: 0.926 AC XY: 68957 AN XY: 74472

African (AFR) AF: 0.773 AC: 32085 AN: 41524

American (AMR) AF: 0.969 AC: 14834 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.991 AC: 3441 AN: 3472

East Asian (EAS) AF: 0.959 AC: 4974 AN: 5188

South Asian (SAS) AF: 0.948 AC: 4578 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10623 AN: 10626

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.985 AC: 67038 AN: 68036

Other (OTH) AF: 0.954 AC: 2017 AN: 2114

Alfa AF: 0.968 Hom.: 54268

Bravo AF: 0.915

Asia WGS AF: 0.936 AC: 3257 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 08, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.46
DANN	Benign	0.41
PhyloP100		-1.0
Mutation Taster		=90/10	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1545650; hg19: chr12-53701104;