19-1783126-T-C

Variant summary

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

The NM_138813.4(ATP8B3):c.3805A>G(p.Ile1269Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,613,432 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: ATP8B3 NM_138813.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56

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=0.097675115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B3	NM_138813.4	c.3805A>G	p.Ile1269Val	missense_variant	29/29	ENST00000310127.10
ATP8B3	NM_001178002.3	c.3694A>G	p.Ile1232Val	missense_variant	29/29
ATP8B3	NR_047593.3	n.4188A>G		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B3	ENST00000310127.10	c.3805A>G	p.Ile1269Val	missense_variant	29/29	1	NM_138813.4	A2
ATP8B3	ENST00000525591.5	c.3694A>G	p.Ile1232Val	missense_variant	29/29	1		P2
ATP8B3	ENST00000531925.5	c.*3688A>G		3_prime_UTR_variant, NMD_transcript_variant	29/29	2

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151806 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000804 AC: 20 AN: 248782 Hom.: 0 AF XY: 0.0000518 AC XY: 7 AN XY: 135134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000134 AC: 196 AN: 1461626 Hom.: 1 Cov.: 31 AF XY: 0.000127 AC XY: 92 AN XY: 727082

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000158

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000593 AC: 9 AN: 151806 Hom.: 0 Cov.: 31 AF XY: 0.0000540 AC XY: 4 AN XY: 74098

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000661 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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

Apr 25, 2023

The c.3805A>G (p.I1269V) alteration is located in exon 29 (coding exon 28) of the ATP8B3 gene. This alteration results from a A to G substitution at nucleotide position 3805, causing the isoleucine (I) at amino acid position 1269 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	0.093
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Benign	0.73
DEOGEN2	Benign	0.050	T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.18
Sift	Benign	0.50	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.070	B;.
Vest4		0.083
MVP		0.72
MPC		0.087
ClinPred		0.14	T
GERP RS		4.6
Varity_R		0.081
gMVP		0.32

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: rs775958143; hg19: chr19-1783125; COSMIC: COSV59545528; COSMIC: COSV59545528;