NM_001183.6:c.65G>T

Variant names:

• chrX-154428757-G-T
• rs781970321
• NM_001183.6:c.65G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001183.6(ATP6AP1):​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 0.0000177 in 113,093 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ATP6AP1 NM_001183.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.146
• Publications: 1 publications found

Genes affected

ATP6AP1 (HGNC:868): (ATPase H+ transporting accessory protein 1) This gene encodes a component of a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. Vacuolar ATPase (V-ATPase) is comprised of a cytosolic V1 (site of the ATP catalytic site) and a transmembrane V0 domain. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. The encoded protein of this gene may assist in the V-ATPase-mediated acidification of neuroendocrine secretory granules. This protein may also play a role in early development. [provided by RefSeq, Aug 2013]

ATP6AP1-DT (HGNC:25138): (ATP6AP1 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00434047).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001183.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP1	NM_001183.6	MANE Select	c.65G>T	p.Arg22Leu	missense	Exon 1 of 10	NP_001174.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP1	ENST00000369762.7	TSL:1 MANE Select	c.65G>T	p.Arg22Leu	missense	Exon 1 of 10	ENSP00000358777.2	Q15904
	ATP6AP1	ENST00000945275.1		c.65G>T	p.Arg22Leu	missense	Exon 1 of 11	ENSP00000615334.1
	ATP6AP1	ENST00000862438.1		c.65G>T	p.Arg22Leu	missense	Exon 1 of 10	ENSP00000532497.1

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 113047 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000138 AC: 1 AN: 72492 AF XY: 0.0000477

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000679

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1022445 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 330049

African (AFR) AF: 0.00 AC: 0 AN: 21473

American (AMR) AF: 0.00 AC: 0 AN: 23948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17515

East Asian (EAS) AF: 0.00 AC: 0 AN: 24458

South Asian (SAS) AF: 0.00 AC: 0 AN: 47540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3846

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 810908

Other (OTH) AF: 0.00 AC: 0 AN: 43185

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 113093 Hom.: 0 Cov.: 24 AF XY: 0.0000284 AC XY: 1 AN XY: 35255

African (AFR) AF: 0.00 AC: 0 AN: 30968

American (AMR) AF: 0.000184 AC: 2 AN: 10863

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53371

Other (OTH) AF: 0.00 AC: 0 AN: 1552

ExAC AF: 0.0000439 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.3
DANN	Benign	0.67
DEOGEN2	Benign	0.045	T
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.15
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.011
Sift	Benign	0.29	T
Sift4G	Uncertain	0.043	D
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.29		Loss of MoRF binding (P = 0.0083)
MVP		0.11
MPC		0.34
ClinPred		0.030	T
GERP RS		-1.6
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.17
Mutation Taster		=97/3	polymorphism

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: rs781970321; hg19: chrX-153657103;