19-1783197-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138813.4(ATP8B3):c.3734C>G(p.Ser1245Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP8B3 NM_138813.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2797257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B3	NM_138813.4	c.3734C>G	p.Ser1245Cys	missense_variant	29/29	ENST00000310127.10
ATP8B3	NM_001178002.3	c.3623C>G	p.Ser1208Cys	missense_variant	29/29
ATP8B3	NR_047593.3	n.4117C>G		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B3	ENST00000310127.10	c.3734C>G	p.Ser1245Cys	missense_variant	29/29	1	NM_138813.4	A2
ATP8B3	ENST00000525591.5	c.3623C>G	p.Ser1208Cys	missense_variant	29/29	1		P2
ATP8B3	ENST00000531925.5	c.*3617C>G		3_prime_UTR_variant, NMD_transcript_variant	29/29	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460774 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

GnomAD4 genome Cov.: 31

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

Jul 12, 2022

The c.3734C>G (p.S1245C) alteration is located in exon 29 (coding exon 28) of the ATP8B3 gene. This alteration results from a C to G substitution at nucleotide position 3734, causing the serine (S) at amino acid position 1245 to be replaced by a cysteine (C). 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	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	0.063
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.082
Sift	Benign	0.063	T;T
Sift4G	Benign	0.070	T;T
Polyphen		1.0	D;.
Vest4		0.18
MutPred		0.38		Loss of phosphorylation at S1245 (P = 0.0042);.;
MVP		0.66
MPC		0.38
ClinPred		0.69	D
GERP RS		3.5
Varity_R		0.073
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1783196;