18-79069424-T-G

Variant summary

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

The NM_198531.5(ATP9B):c.14T>G(p.Ile5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,365,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000081 (0 hom.)
• Consequence: ATP9B NM_198531.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

Genes affected

ATP9B (HGNC:13541): (ATPase phospholipid transporting 9B (putative)) Predicted to enable ATPase-coupled intramembrane lipid transporter activity. Predicted to be involved in endocytosis; phospholipid translocation; and retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum. Located in perinuclear region of cytoplasm and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

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=0.4063927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP9B	NM_198531.5	c.14T>G	p.Ile5Ser	missense_variant	1/30	ENST00000426216.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP9B	ENST00000426216.6	c.14T>G	p.Ile5Ser	missense_variant	1/30	5	NM_198531.5	A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000805 AC: 11 AN: 1365898 Hom.: 0 Cov.: 31 AF XY: 0.00000740 AC XY: 5 AN XY: 676014

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: 0.0000103

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

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

Jun 29, 2023

The c.14T>G (p.I5S) alteration is located in exon 1 (coding exon 1) of the ATP9B gene. This alteration results from a T to G substitution at nucleotide position 14, causing the isoleucine (I) at amino acid position 5 to be replaced by a serine (S). 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	0.68
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.85	T;D;D;T;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	0.90	D;D;D
PrimateAI	Pathogenic	0.92	D
Sift4G	Pathogenic	0.0	D;T;T;D;D
Polyphen		0.96, 0.98, 1.0	.;D;D;.;D
Vest4		0.50, 0.47, 0.50
MVP		0.86
MPC		1.0
ClinPred		0.89	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.60

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

Other links and lift over

dbSNP: rs376573401; hg19: chr18-76829424;