X-154428717-C-G

Variant names:

• chrX-154428717-C-G
• rs1557196220
• NM_001183.6:c.25C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001183.6(ATP6AP1):​c.25C>G​(p.Arg9Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000966 in 1,035,477 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.7e-7 (0 hom. 0 hem.)
• Consequence: ATP6AP1 NM_001183.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.310
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10471454).

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.25C>G	p.Arg9Gly	missense	Exon 1 of 10	NP_001174.2
	ATP6AP1-DT	NR_103768.1		n.-238G>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP1	ENST00000369762.7	TSL:1 MANE Select	c.25C>G	p.Arg9Gly	missense	Exon 1 of 10	ENSP00000358777.2	Q15904
	ATP6AP1	ENST00000945275.1		c.25C>G	p.Arg9Gly	missense	Exon 1 of 11	ENSP00000615334.1
	ATP6AP1	ENST00000862438.1		c.25C>G	p.Arg9Gly	missense	Exon 1 of 10	ENSP00000532497.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 9.66e-7 AC: 1 AN: 1035477 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 336275

African (AFR) AF: 0.00 AC: 0 AN: 22632

American (AMR) AF: 0.00 AC: 0 AN: 27110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18177

East Asian (EAS) AF: 0.00 AC: 0 AN: 25322

South Asian (SAS) AF: 0.00 AC: 0 AN: 49236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3980

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 815025

Other (OTH) AF: 0.00 AC: 0 AN: 43833

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.5
DANN	Benign	0.82
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.31
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.071
Sift	Uncertain	0.016	D
Sift4G	Benign	0.25	T
Polyphen		0.18	B
Vest4		0.31
MutPred		0.37		Loss of methylation at R9 (P = 0.0129)
MVP		0.14
MPC		0.34
ClinPred		0.062	T
GERP RS		1.3
PromoterAI		0.023	Neutral
Varity_R		0.14
gMVP		0.57
Mutation Taster		=94/6	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: rs1557196220; hg19: chrX-153657063;