Genetic Variant ATP8B3:p.Phe1254Leu (chr19-1783171-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_138813.4(ATP8B3):c.3760T>C(p.Phe1254Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ATP8B3
NM_138813.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.71

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP8B3	NM_138813.4 link	c.3760T>C	p.Phe1254Leu	missense_variant	Exon 29 of 29	ENST00000310127.10	NP_620168.1	O60423-2
ATP8B3	NM_001178002.3 link	c.3649T>C	p.Phe1217Leu	missense_variant	Exon 29 of 29		NP_001171473.1	O60423-3
ATP8B3	NR_047593.3 link	n.4143T>C		non_coding_transcript_exon_variant	Exon 29 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATP8B3	ENST00000310127.10 link	c.3760T>C	p.Phe1254Leu	missense_variant	Exon 29 of 29	1	NM_138813.4	ENSP00000311336.6	O60423-2
ATP8B3	ENST00000525591.5 link	c.3649T>C	p.Phe1217Leu	missense_variant	Exon 29 of 29	1		ENSP00000437115.1	O60423-3
ATP8B3	ENST00000531925.5 link	n.*3643T>C		non_coding_transcript_exon_variant	Exon 29 of 29	2		ENSP00000444334.1	F5GZM8
ATP8B3	ENST00000531925.5 link	n.*3643T>C		3_prime_UTR_variant	Exon 29 of 29	2		ENSP00000444334.1	F5GZM8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248610

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461584

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727058

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3760T>C (p.F1254L) alteration is located in exon 29 (coding exon 28) of the ATP8B3 gene. This alteration results from a T to C substitution at nucleotide position 3760, causing the phenylalanine (F) at amino acid position 1254 to be replaced by a leucine (L). 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

0.98

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Uncertain

0.0045

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.046

D;D

Polyphen

1.0

D;.

Vest4

0.39

MutPred

0.70

Gain of loop (P = 0.069);.;

MVP

0.83

MPC

0.27

ClinPred

0.99

GERP RS

4.6

Varity_R

0.66

gMVP

0.57

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