19-1785483-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_138813.4(ATP8B3):c.3379T>C(p.Ser1127Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ATP8B3
NM_138813.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.33

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATP8B3	NM_138813.4 linkuse as main transcript	c.3379T>C	p.Ser1127Pro	missense_variant	26/29	ENST00000310127.10
ATP8B3	NM_001178002.3 linkuse as main transcript	c.3268T>C	p.Ser1090Pro	missense_variant	26/29
ATP8B3	NR_047593.3 linkuse as main transcript	n.3762T>C		non_coding_transcript_exon_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B3	ENST00000310127.10 linkuse as main transcript	c.3379T>C	p.Ser1127Pro	missense_variant	26/29	1	NM_138813.4	A2	O60423-2
ATP8B3	ENST00000525591.5 linkuse as main transcript	c.3268T>C	p.Ser1090Pro	missense_variant	26/29	1		P2	O60423-3
ATP8B3	ENST00000531925.5 linkuse as main transcript	c.*3262T>C		3_prime_UTR_variant, NMD_transcript_variant	26/29	2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460604

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726588

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

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

Jan 16, 2024

The c.3379T>C (p.S1127P) alteration is located in exon 26 (coding exon 25) of the ATP8B3 gene. This alteration results from a T to C substitution at nucleotide position 3379, causing the serine (S) at amino acid position 1127 to be replaced by a proline (P). 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

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.20

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-0.090

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.57

T;T

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Benign

-0.84

MutationAssessor

Pathogenic

3.3

M;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.4

D;D

REVEL

Benign

0.27

Sift

Uncertain

0.018

D;D

Sift4G

Benign

0.12

T;T

Polyphen

1.0

D;.

Vest4

0.72

MutPred

0.78

Gain of catalytic residue at L1126 (P = 0.2231);.;

MVP

0.69

MPC

0.47

ClinPred

0.98

GERP RS

2.3

Varity_R

0.68

gMVP

0.75

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