NM_005765.3:c.-35G>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• syndromic X-linked intellectual disability Hedera type

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

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.01).
• BP6: Variant X-40581031-G-C is Benign according to our data. Variant chrX-40581031-G-C is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 XL,AR,Unknown gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	NM_005765.3	MANE Select	c.-35G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_005756.2
	ATP6AP2	NM_005765.3	MANE Select	c.-35G>C		5_prime_UTR	Exon 1 of 9	NP_005756.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP6AP2	ENST00000636580.2	TSL:1 MANE Select	c.-35G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000490083.1	O75787-1
	ATP6AP2	ENST00000636580.2	TSL:1 MANE Select	c.-35G>C		5_prime_UTR	Exon 1 of 9	ENSP00000490083.1	O75787-1
	ATP6AP2	ENST00000636639.1	TSL:1	n.-35G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000490382.1	A0A1B0GV60

Frequencies

GnomAD3 genomes AF: 0.00994 AC: 1125 AN: 113235 Hom.: 18 Cov.: 24

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

GnomAD2 exomes AF: 0.00237 AC: 245 AN: 103268 AF XY: 0.00149

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 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

African (AFR) AF: 0.0393 AC: 975 AN: 24830

American (AMR) AF: 0.00147 AC: 41 AN: 27853

Ashkenazi Jewish (ASJ) AF: 0.0000539 AC: 1 AN: 18560

East Asian (EAS) AF: 0.00 AC: 0 AN: 27074

South Asian (SAS) AF: 0.000141 AC: 7 AN: 49787

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35617

Middle Eastern (MID) AF: 0.00112 AC: 4 AN: 3560

European-Non Finnish (NFE) AF: 0.0000183 AC: 15 AN: 817979

Other (OTH) AF: 0.00258 AC: 114 AN: 44200

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

African (AFR) AF: 0.0342 AC: 1072 AN: 31308

American (AMR) AF: 0.00330 AC: 36 AN: 10897

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6297

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000938 AC: 5 AN: 53301

Other (OTH) AF: 0.00840 AC: 13 AN: 1547

Alfa AF: 0.00543 Hom.: 22

Bravo AF: 0.0121

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.7
DANN	Benign	0.84
PhyloP100		0.0060
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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: rs111632930; hg19: chrX-40440283;