4-42522246-C-T

Position:

• chr4-42522246-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006095.2(ATP8A1):​c.1861G>A​(p.Glu621Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP8A1 NM_006095.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02

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

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=0.35136092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8A1	NM_006095.2	c.1861G>A	p.Glu621Lys	missense_variant	22/37	ENST00000381668.9	NP_006086.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8A1	ENST00000381668.9	c.1861G>A	p.Glu621Lys	missense_variant	22/37	1	NM_006095.2	ENSP00000371084.5
ATP8A1	ENST00000264449.14	c.1816G>A	p.Glu606Lys	missense_variant	21/36	1		ENSP00000264449.10
ATP8A1	ENST00000700470.1	c.1816G>A	p.Glu606Lys	missense_variant	21/36			ENSP00000515003.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.1861G>A (p.E621K) alteration is located in exon 22 (coding exon 22) of the ATP8A1 gene. This alteration results from a G to A substitution at nucleotide position 1861, causing the glutamic acid (E) at amino acid position 621 to be replaced by a lysine (K). 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	Benign	0.14
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.23
Sift	Benign	0.17	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.025	B;.
Vest4		0.52
MutPred		0.47		Gain of MoRF binding (P = 0.0075);.;
MVP		0.57
MPC		0.70
ClinPred		0.63	D
GERP RS		5.5
Varity_R		0.26
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1726208716; hg19: chr4-42524263;