4-42503502-T-C

Position:

• chr4-42503502-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006095.2(ATP8A1):​c.2099A>G​(p.Lys700Arg) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP8A1 NM_006095.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18467522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8A1	NM_006095.2	c.2099A>G	p.Lys700Arg	missense_variant	24/37	ENST00000381668.9	NP_006086.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP8A1	ENST00000381668.9	c.2099A>G	p.Lys700Arg	missense_variant	24/37	1	NM_006095.2	ENSP00000371084.5
ATP8A1	ENST00000264449.14	c.2054A>G	p.Lys685Arg	missense_variant	23/36	1		ENSP00000264449.10
ATP8A1	ENST00000514372.5	n.152A>G		non_coding_transcript_exon_variant	2/14	1		ENSP00000426495.1
ATP8A1	ENST00000700470.1	c.2054A>G	p.Lys685Arg	missense_variant	23/36			ENSP00000515003.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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 23, 2024

The c.2099A>G (p.K700R) alteration is located in exon 24 (coding exon 24) of the ATP8A1 gene. This alteration results from a A to G substitution at nucleotide position 2099, causing the lysine (K) at amino acid position 700 to be replaced by an arginine (R). 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	0.065
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.80
DEOGEN2	Benign	0.060	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.48	N;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.17	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.70	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.0080	B;.
Vest4		0.22
MutPred		0.54		Loss of methylation at K700 (P = 0.011);.;
MVP		0.40
MPC		0.57
ClinPred		0.51	D
GERP RS		4.4
Varity_R		0.050
gMVP		0.58

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: rs907086262; hg19: chr4-42505519;