Genetic Variant NM_015665.6:c.*169A>G (chr12-53307320-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.01

Variant links:

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 links:

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]

MYG1 links:

ENSG00000288663 (HGNC:):

ENSG00000288663 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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	Effect	MANE	Protein	UniProt
AAAS	NM_015665.6 link	c.*169A>G	downstream_gene_variant	ENST00000209873.9	NP_056480.1	Q9NRG9-1
MYG1	NM_021640.4 link	c.*171T>C	downstream_gene_variant	ENST00000267103.10	NP_067653.4	Q9HB07
AAAS	NM_001173466.2 link	c.*169A>G	downstream_gene_variant		NP_001166937.1	Q9NRG9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AAAS	ENST00000209873.9 link	c.*169A>G		downstream_gene_variant		1	NM_015665.6	ENSP00000209873.4		Q9NRG9-1
MYG1	ENST00000267103.10 link	c.*171T>C		downstream_gene_variant		1	NM_021640.4	ENSP00000267103.5		Q9HB07

Frequencies

GnomAD3 genomes

AF:

0.924

AC:

140681

AN:

152178

Hom.:

65725

Cov.:

show subpopulations

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.:

AF XY:

0.978

AC XY:

475413

AN XY:

486284

show subpopulations

Gnomad4 AFR exome

AF:

0.759

Gnomad4 AMR exome

AF:

0.979

Gnomad4 ASJ exome

AF:

0.990

Gnomad4 EAS exome

AF:

0.979

Gnomad4 SAS exome

AF:

0.952

Gnomad4 FIN exome

AF:

0.998

Gnomad4 NFE exome

AF:

0.986

Gnomad4 OTH exome

AF:

0.966

GnomAD4 genome

AF:

0.924

AC:

140774

AN:

152296

Hom.:

65762

Cov.:

AF XY:

0.926

AC XY:

68957

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.773

Gnomad4 AMR

AF:

0.969

Gnomad4 ASJ

AF:

0.991

Gnomad4 EAS

AF:

0.959

Gnomad4 SAS

AF:

0.948

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.985

Gnomad4 OTH

AF:

0.954

Alfa

AF:

0.969

Hom.:

45268

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

LINK: link

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over