15-49862318-G-A

Variant summary

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

The NM_024837.4(ATP8B4):c.3224C>T(p.Thr1075Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1075A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP8B4 NM_024837.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

Genes affected

ATP8B4 (HGNC:13536): (ATPase phospholipid transporting 8B4 (putative)) This gene encodes a member of the cation transport ATPase (P-type) family and type IV subfamily. The encoded protein is involved in phospholipid transport in the cell membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

ACMG classification

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/exons	MANE	UniProt
ATP8B4	NM_024837.4	c.3224C>T	p.Thr1075Ile	missense_variant	27/28	ENST00000284509.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP8B4	ENST00000284509.11	c.3224C>T	p.Thr1075Ile	missense_variant	27/28	5	NM_024837.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Aug 17, 2022

The c.3224C>T (p.T1075I) alteration is located in exon 27 (coding exon 26) of the ATP8B4 gene. This alteration results from a C to T substitution at nucleotide position 3224, causing the threonine (T) at amino acid position 1075 to be replaced by an isoleucine (I). 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	0.13
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0026	T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.73	T;.
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.17
Sift	Benign	0.28	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.012	B;B
Vest4		0.59
MutPred		0.44		Loss of catalytic residue at T1075 (P = 0.0302);Loss of catalytic residue at T1075 (P = 0.0302);
MVP		0.73
MPC		0.15
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.20
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-50154515; COSMIC: COSV52720867;