rs1557196978

Variant names:

• chrX-154432444-T-G
• rs1557196978
• NM_001183.6:c.542T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001183.6(ATP6AP1):​c.542T>G​(p.Leu181Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L181L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: ATP6AP1 NM_001183.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.27
• Publications: 3 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 Gene-Disease associations (from GenCC):

• immunodeficiency 47

  Inheritance: XL, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital disorder of glycosylation type II

  Inheritance: XL Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant X-154432444-T-G is Pathogenic according to our data. Variant chrX-154432444-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437913.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP1	NM_001183.6	MANE Select	c.542T>G	p.Leu181Arg	missense	Exon 4 of 10	NP_001174.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP1	ENST00000369762.7	TSL:1 MANE Select	c.542T>G	p.Leu181Arg	missense	Exon 4 of 10	ENSP00000358777.2
	ATP6AP1	ENST00000619046.5	TSL:1	c.173+129T>G		intron	N/A	ENSP00000482243.2
	ATP6AP1	ENST00000449556.5	TSL:5	c.542T>G	p.Leu181Arg	missense	Exon 4 of 7	ENSP00000392375.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Immunodeficiency 47 (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.84		Loss of stability (P = 0.0158)
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.98
Mutation Taster		=22/78	disease causing (ClinVar)

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: rs1557196978; hg19: chrX-153660790;