19-1785576-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138813.4(ATP8B3):c.3286A>C(p.Met1096Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,612,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ATP8B3 NM_138813.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.39

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 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=0.042140335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP8B3	NM_138813.4	c.3286A>C	p.Met1096Leu	missense_variant	26/29	ENST00000310127.10
ATP8B3	NM_001178002.3	c.3175A>C	p.Met1059Leu	missense_variant	26/29
ATP8B3	NR_047593.3	n.3669A>C		non_coding_transcript_exon_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B3	ENST00000310127.10	c.3286A>C	p.Met1096Leu	missense_variant	26/29	1	NM_138813.4	A2
ATP8B3	ENST00000525591.5	c.3175A>C	p.Met1059Leu	missense_variant	26/29	1		P2
ATP8B3	ENST00000526847.1	c.*753A>C		3_prime_UTR_variant, NMD_transcript_variant	5/5	3
ATP8B3	ENST00000531925.5	c.*3169A>C		3_prime_UTR_variant, NMD_transcript_variant	26/29	2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD3 exomes AF: 0.0000484 AC: 12 AN: 247932 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134894

Gnomad AFR exome AF: 0.000648

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460772 Hom.: 0 Cov.: 37 AF XY: 0.0000165 AC XY: 12 AN XY: 726676

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74356

Gnomad4 AFR AF: 0.000700

Gnomad4 AMR AF: 0.00

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

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.00141 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000661 AC: 8

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

Dec 02, 2022

The c.3286A>C (p.M1096L) alteration is located in exon 26 (coding exon 25) of the ATP8B3 gene. This alteration results from a A to C substitution at nucleotide position 3286, causing the methionine (M) at amino acid position 1096 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	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.039
Dann	Benign	0.71
DEOGEN2	Benign	0.035	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.10	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.053
Sift	Benign	0.091	T;T
Sift4G	Benign	0.092	T;T
Polyphen		0.0	B;.
Vest4		0.10
MutPred		0.40		Loss of helix (P = 0.2271);.;
MVP		0.33
MPC		0.072
ClinPred		0.0087	T
GERP RS		-6.5
Varity_R		0.11
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs199528887; hg19: chr19-1785575; COSMIC: COSV59545552; COSMIC: COSV59545552;