19-1784944-C-T

Position:

chr19-1784944-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138813.4(ATP8B3):c.3535G>A(p.Ala1179Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000976 in 1,608,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

ATP8B3
NM_138813.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

Variant links:

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]

ATP8B3 links:

ATP8B3 (HGNC:):

ATP8B3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05007419).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP8B3	NM_138813.4 linkuse as main transcript	c.3535G>A	p.Ala1179Thr	missense_variant, splice_region_variant	28/29	ENST00000310127.10	NP_620168.1	O60423-2
ATP8B3	NM_001178002.3 linkuse as main transcript	c.3424G>A	p.Ala1142Thr	missense_variant, splice_region_variant	28/29		NP_001171473.1	O60423-3
ATP8B3	NR_047593.3 linkuse as main transcript	n.3918G>A		splice_region_variant, non_coding_transcript_exon_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ATP8B3	ENST00000310127.10 linkuse as main transcript	c.3535G>A	p.Ala1179Thr	missense_variant, splice_region_variant	28/29	1	NM_138813.4	ENSP00000311336.6	O60423-2
ATP8B3	ENST00000525591.5 linkuse as main transcript	c.3424G>A	p.Ala1142Thr	missense_variant, splice_region_variant	28/29	1		ENSP00000437115.1	O60423-3
ATP8B3	ENST00000531925.5 linkuse as main transcript	n.*3418G>A		splice_region_variant, non_coding_transcript_exon_variant	28/29	2		ENSP00000444334.1	F5GZM8
ATP8B3	ENST00000531925.5 linkuse as main transcript	n.*3418G>A		3_prime_UTR_variant	28/29	2		ENSP00000444334.1	F5GZM8

Frequencies

GnomAD3 genomes

AF:

0.0000659

AC:

AN:

151772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000590

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000120

AC:

AN:

242002

Hom.:

AF XY:

0.000129

AC XY:

AN XY:

131508

show subpopulations

Gnomad AFR exome

AF:

0.0000660

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000541

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000731

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

147

AN:

1456808

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

724332

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000899

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000550

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000811

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000590

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000726

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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 submitter

clinical testing

Ambry Genetics

Oct 21, 2024

The c.3535G>A (p.A1179T) alteration is located in exon 28 (coding exon 27) of the ATP8B3 gene. This alteration results from a G to A substitution at nucleotide position 3535, causing the alanine (A) at amino acid position 1179 to be replaced by a threonine (T). 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

0.15

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.2

L;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.39

Sift

Benign

1.0

T;T

Sift4G

Benign

0.85

T;T

Polyphen

0.98

D;.

Vest4

0.12

MutPred

0.53

Loss of stability (P = 0.0618);.;

MVP

0.91

MPC

0.38

ClinPred

0.26

GERP RS

4.7

Varity_R

0.10

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over