19-1784836-T-G

Variant summary

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

The NM_138813.4(ATP8B3):c.3643A>C(p.Lys1215Gln) variant causes a missense 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. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATP8B3 NM_138813.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.247

Genes affected

ATP8B3 (HGNC:13535): (ATPase phospholipid transporting 8B3) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of aminophospholipid-transporting ATPases. The aminophospholipid translocases transport phosphatidylserine and phosphatidylethanolamine from one side of a bilayer to the other. This gene encodes member 3 of phospholipid-transporting ATPase 8B; other members of this protein family are located on chromosomes 1, 15 and 18. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

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=0.15176606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B3	NM_138813.4	c.3643A>C	p.Lys1215Gln	missense_variant	28/29	ENST00000310127.10
ATP8B3	NM_001178002.3	c.3532A>C	p.Lys1178Gln	missense_variant	28/29
ATP8B3	NR_047593.3	n.4026A>C		non_coding_transcript_exon_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B3	ENST00000310127.10	c.3643A>C	p.Lys1215Gln	missense_variant	28/29	1	NM_138813.4	A2
ATP8B3	ENST00000525591.5	c.3532A>C	p.Lys1178Gln	missense_variant	28/29	1		P2
ATP8B3	ENST00000531925.5	c.*3526A>C		3_prime_UTR_variant, NMD_transcript_variant	28/29	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000423 AC: 1 AN: 236536 Hom.: 0 AF XY: 0.00000779 AC XY: 1 AN XY: 128448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000572

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.87e-7 AC: 1 AN: 1455216 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

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

May 09, 2023

The c.3643A>C (p.K1215Q) alteration is located in exon 28 (coding exon 27) of the ATP8B3 gene. This alteration results from a A to C substitution at nucleotide position 3643, causing the lysine (K) at amino acid position 1215 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	7.8
Dann	Benign	0.93
DEOGEN2	Benign	0.071	T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.36	T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.083
Sift	Benign	0.32	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.94	P;.
Vest4		0.26
MutPred		0.48		Loss of methylation at K1215 (P = 0.0058);.;
MVP		0.45
MPC		0.22
ClinPred		0.33	T
GERP RS		1.0
Varity_R		0.060
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761753808; hg19: chr19-1784835; COSMIC: COSV59539817; COSMIC: COSV59539817;