18-79069475-G-T

Position:

• chr18-79069475-G-T

Variant summary

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

The NM_198531.5(ATP9B):​c.65G>T​(p.Arg22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000074 in 1,350,550 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: 35)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ATP9B NM_198531.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.82

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=0.27545223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP9B	NM_198531.5	c.65G>T	p.Arg22Leu	missense_variant	1/30	ENST00000426216.6	NP_940933.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP9B	ENST00000426216.6	c.65G>T	p.Arg22Leu	missense_variant	1/30	5	NM_198531.5	ENSP00000398076	A1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.40e-7 AC: 1 AN: 1350550 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 666516

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: 9.43e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

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

Jan 18, 2022

The c.65G>T (p.R22L) alteration is located in exon 1 (coding exon 1) of the ATP9B gene. This alteration results from a G to T substitution at nucleotide position 65, causing the arginine (R) at amino acid position 22 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	0.23
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	.;T;.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.84	T;T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.1	.;L;L;.;.
MutationTaster	Benign	0.71	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.51	.;N;N;.;.
REVEL	Benign	0.26
Sift	Uncertain	0.010	.;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.039, 0.065, 0.92	.;B;B;.;P
Vest4		0.37, 0.36, 0.36
MVP		0.80
MPC		0.30
ClinPred		0.65	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.58

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: rs911658150; hg19: chr18-76829475;