19-1783186-G-T

Variant names:

• chr19-1783186-G-T
• rs777966827
• NM_138813.4:c.3745C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138813.4(ATP8B3):​c.3745C>A​(p.Arg1249Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,184 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1249C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATP8B3 NM_138813.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.40
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138813.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8B3	NM_138813.4	MANE Select	c.3745C>A	p.Arg1249Ser	missense	Exon 29 of 29	NP_620168.1	O60423-2
	ATP8B3	NM_001178002.3		c.3634C>A	p.Arg1212Ser	missense	Exon 29 of 29	NP_001171473.1	O60423-3
	ATP8B3	NR_047593.3		n.4128C>A		non_coding_transcript_exon	Exon 29 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8B3	ENST00000310127.10	TSL:1 MANE Select	c.3745C>A	p.Arg1249Ser	missense	Exon 29 of 29	ENSP00000311336.6	O60423-2
	ATP8B3	ENST00000525591.5	TSL:1	c.3634C>A	p.Arg1212Ser	missense	Exon 29 of 29	ENSP00000437115.1	O60423-3
	ATP8B3	ENST00000531925.5	TSL:2	n.*3628C>A		non_coding_transcript_exon	Exon 29 of 29	ENSP00000444334.1	F5GZM8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461184 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726790

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111700

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.048	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.4
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.45		Gain of phosphorylation at R1249 (P = 0.005)
MVP		0.84
MPC		0.46
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.77
gMVP		0.70
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs777966827; hg19: chr19-1783185;