4-42455599-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006095.2(ATP8A1):​c.2620A>G​(p.Ile874Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP8A1
NM_006095.2 missense, splice_region

Scores

1
4
14
Splicing: ADA: 0.0001803
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.19
Variant links:
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]

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ACMG classification

Classification made for transcript

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=0.17349991).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP8A1NM_006095.2 linkuse as main transcriptc.2620A>G p.Ile874Val missense_variant, splice_region_variant 28/37 ENST00000381668.9 NP_006086.1 Q9Y2Q0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP8A1ENST00000381668.9 linkuse as main transcriptc.2620A>G p.Ile874Val missense_variant, splice_region_variant 28/371 NM_006095.2 ENSP00000371084.5 Q9Y2Q0-1

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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 27, 2024The c.2620A>G (p.I874V) alteration is located in exon 28 (coding exon 28) of the ATP8A1 gene. This alteration results from a A to G substitution at nucleotide position 2620, causing the isoleucine (I) at amino acid position 874 to be replaced by a valine (V). 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
Benign
-0.047
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.078
T;.
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.054
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
0.075
N;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.94
N;N
REVEL
Benign
0.29
Sift
Uncertain
0.022
D;D
Sift4G
Uncertain
0.025
D;D
Polyphen
0.0
B;.
Vest4
0.13
MutPred
0.61
Loss of helix (P = 0.079);.;
MVP
0.30
MPC
0.40
ClinPred
0.47
T
GERP RS
4.2
Varity_R
0.18
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00018
dbscSNV1_RF
Benign
0.0040
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-42457616; API