chr4-42485566-C-A

Variant names:

• chr4-42485566-C-A
• NM_006095.2:c.2254G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006095.2(ATP8A1):​c.2254G>T​(p.Ala752Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,496 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A752T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP8A1 NM_006095.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

ATP8A1 (HGNC:13531): (ATPase phospholipid transporting 8A1) The P-type adenosinetriphosphatases (P-type ATPases) are a family of proteins which use the free energy of ATP hydrolysis to drive uphill transport of ions across membranes. Several subfamilies of P-type ATPases have been identified. One subfamily catalyzes transport of heavy metal ions. Another subfamily transports non-heavy metal ions (NMHI). The protein encoded by this gene is a member of the third subfamily of P-type ATPases and acts to transport amphipaths, such as phosphatidylserine. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006095.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A1	NM_006095.2	MANE Select	c.2254G>T	p.Ala752Ser	missense	Exon 25 of 37	NP_006086.1	Q9Y2Q0-1
	ATP8A1	NM_001400024.1		c.2254G>T	p.Ala752Ser	missense	Exon 25 of 37	NP_001386953.1
	ATP8A1	NM_001400025.1		c.2230G>T	p.Ala744Ser	missense	Exon 25 of 37	NP_001386954.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A1	ENST00000381668.9	TSL:1 MANE Select	c.2254G>T	p.Ala752Ser	missense	Exon 25 of 37	ENSP00000371084.5	Q9Y2Q0-1
	ATP8A1	ENST00000264449.14	TSL:1	c.2209G>T	p.Ala737Ser	missense	Exon 24 of 36	ENSP00000264449.10	Q9Y2Q0-3
	ATP8A1	ENST00000514372.5	TSL:1	n.204+17884G>T		intron	N/A	ENSP00000426495.1	H0YAA1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461496 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111772

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.58		Gain of helix (P = 0.0117)
MVP		0.60
MPC		1.3
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.59
Mutation Taster		=14/86	disease causing

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

Other links and lift over

hg19: chr4-42487583;