chrX-40581031-G-C

Variant names:

• chrX-40581031-G-C
• rs111632930
• NM_005765.3:c.-35G>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005765.3(ATP6AP2):​c.-35G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,162,744 control chromosomes in the GnomAD database, including 27 homozygotes. There are 622 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0099 (18 hom., 325 hem., cov: 24)
  • Exomes 𝑓: 0.0011 (9 hom. 297 hem.)
• Consequence: ATP6AP2 NM_005765.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00600

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-40581031-G-C is Benign according to our data. Variant chrX-40581031-G-C is described in ClinVar as [Benign]. Clinvar id is 136464.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00994 (1126/113284) while in subpopulation AFR AF= 0.0342 (1072/31308). AF 95% confidence interval is 0.0325. There are 18 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6AP2	NM_005765.3	c.-35G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	ENST00000636580.2	NP_005756.2
ATP6AP2	NM_005765.3	c.-35G>C		5_prime_UTR_variant	Exon 1 of 9	ENST00000636580.2	NP_005756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP6AP2	ENST00000636580	c.-35G>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	1	NM_005765.3	ENSP00000490083.1
ATP6AP2	ENST00000636580	c.-35G>C		5_prime_UTR_variant	Exon 1 of 9	1	NM_005765.3	ENSP00000490083.1

Frequencies

GnomAD3 genomes AF: 0.00994 AC: 1125 AN: 113235 Hom.: 18 Cov.: 24 AF XY: 0.00915 AC XY: 324 AN XY: 35401

Gnomad AFR AF: 0.0343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00331

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: 0.0000938

Gnomad OTH AF: 0.00851

GnomAD3 exomes AF: 0.00237 AC: 245 AN: 103268 Hom.: 1 AF XY: 0.00149 AC XY: 55 AN XY: 36924

Gnomad AFR exome AF: 0.0386

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000355

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000647

GnomAD4 exome AF: 0.00110 AC: 1157 AN: 1049460 Hom.: 9 Cov.: 30 AF XY: 0.000867 AC XY: 297 AN XY: 342370

Gnomad4 AFR exome AF: 0.0393

Gnomad4 AMR exome AF: 0.00147

Gnomad4 ASJ exome AF: 0.0000539

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000141

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000183

Gnomad4 OTH exome AF: 0.00258

GnomAD4 genome AF: 0.00994 AC: 1126 AN: 113284 Hom.: 18 Cov.: 24 AF XY: 0.00917 AC XY: 325 AN XY: 35460

Gnomad4 AFR AF: 0.0342

Gnomad4 AMR AF: 0.00330

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000938

Gnomad4 OTH AF: 0.00840

Alfa AF: 0.00543 Hom.: 22

Bravo AF: 0.0121

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 28, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.7
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

LitVar

Other links and lift over

dbSNP: rs111632930; hg19: chrX-40440283;