rs371560228

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_016529.6(ATP8A2):​c.3439C>T​(p.Arg1147Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000062 in 1,515,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

ATP8A2
NM_016529.6 missense

Scores

4
8
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.13
Variant links:
Genes affected
ATP8A2 (HGNC:13533): (ATPase phospholipid transporting 8A2) The protein encoded by this gene is a member of the P4 ATPase family of proteins, which are thought to be involved in a process called lipid flipping, whereby phospholipids are translocated inwards from the exoplasmic leaflet to the cytosolic leaflet of the cell membrane, which aids in generating and maintaining asymmetry in membrane lipids. This protein is predicted to contain an E1 E2 ATPase, a haloacid dehalogenase-like hydrolase (HAD) domain, and multiple transmembrane domains. Associations between this protein and cell cycle control protein 50A are important for translocation of phosphatidylserine across membranes. Mutations in this gene have been associated with a syndrome (CAMRQ4) characterized by cerebellar ataxia and cognitive disabilities. In addition, a translocation breakpoint within this gene was observed in an individual with neurological dysfunction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.41186732).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP8A2NM_016529.6 linkuse as main transcriptc.3439C>T p.Arg1147Trp missense_variant 36/37 ENST00000381655.7 NP_057613.4 Q9NTI2-4Q6ZU25

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP8A2ENST00000381655.7 linkuse as main transcriptc.3439C>T p.Arg1147Trp missense_variant 36/371 NM_016529.6 ENSP00000371070.2 Q9NTI2-4

Frequencies

GnomAD3 genomes
AF:
0.0000724
AC:
11
AN:
151852
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000726
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000822
AC:
10
AN:
121692
Hom.:
0
AF XY:
0.0000761
AC XY:
5
AN XY:
65674
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.000213
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000609
AC:
83
AN:
1363828
Hom.:
0
Cov.:
32
AF XY:
0.0000536
AC XY:
36
AN XY:
671342
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000344
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000411
Gnomad4 NFE exome
AF:
0.0000742
Gnomad4 OTH exome
AF:
0.0000177
GnomAD4 genome
AF:
0.0000724
AC:
11
AN:
151852
Hom.:
0
Cov.:
31
AF XY:
0.0000809
AC XY:
6
AN XY:
74164
show subpopulations
Gnomad4 AFR
AF:
0.0000726
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000194
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000128
AC:
1
ExAC
AF:
0.0000326
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 09, 2022The c.3439C>T (p.R1147W) alteration is located in exon 36 (coding exon 36) of the ATP8A2 gene. This alteration results from a C to T substitution at nucleotide position 3439, causing the arginine (R) at amino acid position 1147 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicOct 24, 2023PM2_moderate -
Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMar 05, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.066
T
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.057
.;T
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Benign
0.070
D
MetaRNN
Benign
0.41
T;T
MetaSVM
Uncertain
-0.26
T
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-3.3
D;.
REVEL
Uncertain
0.38
Sift
Uncertain
0.0020
D;.
Sift4G
Pathogenic
0.0010
D;D
Vest4
0.46
MVP
0.82
MPC
2.1
ClinPred
0.85
D
GERP RS
5.8
Varity_R
0.14
gMVP
0.57

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.

Other links and lift over

dbSNP: rs371560228; hg19: chr13-26586730; API