rs35540339

Positions:

• chr13-25699239-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016529.6(ATP8A2):​c.2278G>A​(p.Val760Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,540 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (19 hom., cov: 32)
  • Exomes 𝑓: 0.010 (113 hom.)
• Consequence: ATP8A2 NM_016529.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.29

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048558116).
• BP6: Variant 13-25699239-G-A is Benign according to our data. Variant chr13-25699239-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 376887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00854 (1301/152270) while in subpopulation NFE AF= 0.0121 (823/68024). AF 95% confidence interval is 0.0114. There are 19 homozygotes in gnomad4. There are 676 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8A2	NM_016529.6	c.2278G>A	p.Val760Met	missense_variant	25/37	ENST00000381655.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8A2	ENST00000381655.7	c.2278G>A	p.Val760Met	missense_variant	25/37	1	NM_016529.6

Frequencies

GnomAD3 genomes AF: 0.00856 AC: 1302 AN: 152152 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00871 AC: 2167 AN: 248900 Hom.: 23 AF XY: 0.00867 AC XY: 1170 AN XY: 135018

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00297

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00344

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0102 AC: 14947 AN: 1461270 Hom.: 113 Cov.: 30 AF XY: 0.0100 AC XY: 7287 AN XY: 726900

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00307

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00350

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00967

GnomAD4 genome AF: 0.00854 AC: 1301 AN: 152270 Hom.: 19 Cov.: 32 AF XY: 0.00908 AC XY: 676 AN XY: 74462

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00700

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0249

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0104 Hom.: 53

Bravo AF: 0.00634

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00202 AC: 8

ESP6500EA AF: 0.00974 AC: 81

ExAC AF: 0.00841 AC: 1017

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.00820

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ATP8A2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.010	.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.59	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.97	N;.
REVEL	Benign	0.076
Sift	Benign	0.070	T;.
Sift4G	Benign	0.14	T;T
Vest4		0.088
MVP		0.62
MPC		0.96
ClinPred		0.011	T
GERP RS		1.4
Varity_R		0.030
gMVP		0.38

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: rs35540339; hg19: chr13-26273377; COSMIC: COSV99029409;