20-51639348-C-G

Position:

• chr20-51639348-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006045.3(ATP9A):​c.1663G>C​(p.Val555Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,318 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATP9A NM_006045.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98

Genes affected

ATP9A (HGNC:13540): (ATPase phospholipid transporting 9A (putative)) Enables protease binding activity. Involved in negative regulation of exosomal secretion; regulation of endocytic recycling; and regulation of retrograde transport, endosome to Golgi. Located in several cellular components, including endosome membrane; perinuclear region of cytoplasm; and trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP9A. . Gene score misZ 4.1543 (greater than the threshold 3.09). Trascript score misZ 4.4901 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with poor growth and behavioral abnormalities.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP9A	NM_006045.3	c.1663G>C	p.Val555Leu	missense_variant	15/28	ENST00000338821.6	NP_006036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP9A	ENST00000338821.6	c.1663G>C	p.Val555Leu	missense_variant	15/28	1	NM_006045.3	ENSP00000342481.5
ATP9A	ENST00000311637.9	c.1255G>C	p.Val419Leu	missense_variant	10/23	1		ENSP00000309086.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459318 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725874

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.1663G>C (p.V555L) alteration is located in exon 15 (coding exon 15) of the ATP9A gene. This alteration results from a G to C substitution at nucleotide position 1663, causing the valine (V) at amino acid position 555 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	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.51
Sift	Benign	0.17	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.78	.;P
Vest4		0.65
MutPred		0.70		.;Loss of sheet (P = 0.0357);
MVP		0.50
MPC		0.94
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.24
gMVP		0.61

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: chr20-50255887;