chrX-40605752-T-A

Variant names:

• chrX-40605752-T-A
• rs79790275
• NM_005765.3:c.1050T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005765.3(ATP6AP2):​c.1050T>A​(p.Asp350Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,089,943 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D350D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: ATP6AP2 NM_005765.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.746
• Publications: 1 publications found

Genes affected

ATP6AP2 (HGNC:18305): (ATPase H+ transporting accessory protein 2) This gene encodes a protein that is associated with adenosine triphosphatases (ATPases). Proton-translocating ATPases have fundamental roles in energy conservation, secondary active transport, acidification of intracellular compartments, and cellular pH homeostasis. There are three classes of ATPases- F, P, and V. The vacuolar (V-type) ATPases have a transmembrane proton-conducting sector and an extramembrane catalytic sector. The encoded protein has been found associated with the transmembrane sector of the V-type ATPases. [provided by RefSeq, Jul 2008]

ATP6AP2 Gene-Disease associations (from GenCC):

• ATP6AP2-related disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• congenital disorder of glycosylation, type IIr

  Inheritance: AR, XL Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• syndromic X-linked intellectual disability Hedera type

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• X-linked parkinsonism-spasticity syndrome

  Inheritance: XL, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36329114).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005765.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	NM_005765.3	MANE Select	c.1050T>A	p.Asp350Glu	missense	Exon 9 of 9	NP_005756.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	ENST00000636580.2	TSL:1 MANE Select	c.1050T>A	p.Asp350Glu	missense	Exon 9 of 9	ENSP00000490083.1
	ATP6AP2	ENST00000636639.1	TSL:1	n.*503T>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000490382.1
	ATP6AP2	ENST00000636639.1	TSL:1	n.*503T>A		3_prime_UTR	Exon 10 of 10	ENSP00000490382.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183039 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1089943 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 356295

African (AFR) AF: 0.00 AC: 0 AN: 26215

American (AMR) AF: 0.00 AC: 0 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19344

East Asian (EAS) AF: 0.00 AC: 0 AN: 30157

South Asian (SAS) AF: 0.00 AC: 0 AN: 53929

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3677

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 835170

Other (OTH) AF: 0.00 AC: 0 AN: 45792

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.75
PrimateAI	Pathogenic	0.79	T
REVEL	Uncertain	0.35
Polyphen		0.80	P
MutPred		0.57		Loss of MoRF binding (P = 0.1352)
MVP		0.67
MPC		1.4
ClinPred		0.65	D
GERP RS		-0.60
Varity_R		0.90
gMVP		0.89
Mutation Taster		=39/61	disease causing

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

Other links and lift over

dbSNP: rs79790275; hg19: chrX-40465004;