Variant 20-51619001-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The ENST00000338821.6(ATP9A):c.2158C>T(p.Arg720Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ATP9A
ENST00000338821.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87

Variant links:

Genes affected

ATP9A (HGNC:13540): (ATPase phospholipid transporting 9A (putative)) Enables protease binding activity. Involved in negative regulation of exosomal secretion; regulation of endocytic recycling; and regulation of retrograde transport, endosome to Golgi. Located in several cellular components, including endosome membrane; perinuclear region of cytoplasm; and trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATP9A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP9A. . Gene score misZ 4.1543 (greater than the threshold 3.09). Trascript score misZ 4.4901 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with poor growth and behavioral abnormalities.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP9A	NM_006045.3 linkuse as main transcript	c.2158C>T	p.Arg720Cys	missense_variant	20/28	ENST00000338821.6	NP_006036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP9A	ENST00000338821.6 linkuse as main transcript	c.2158C>T	p.Arg720Cys	missense_variant	20/28	1	NM_006045.3	ENSP00000342481	P1	O75110-1
ATP9A	ENST00000311637.9 linkuse as main transcript	c.1750C>T	p.Arg584Cys	missense_variant	15/23	1		ENSP00000309086

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251370

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000270

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.2158C>T (p.R720C) alteration is located in exon 20 (coding exon 20) of the ATP9A gene. This alteration results from a C to T substitution at nucleotide position 2158, causing the arginine (R) at amino acid position 720 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

0.070

MutationAssessor

Pathogenic

3.4

.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

1.0

.;D

Vest4

0.81

MutPred

0.49

.;Loss of loop (P = 0.0075);

MVP

0.54

MPC

2.2

ClinPred

0.97

GERP RS

5.1

Varity_R

0.72

gMVP

0.83

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

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