X-154428787-TGGCGGCGGCGGC-TGGCGGCGGCGGCGGCGGC

Variant names:

• chrX-154428787-T-TGGCGGC
• rs781797236
• NM_001183.6:c.111_116dupGGCGGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001183.6(ATP6AP1):​c.111_116dupGGCGGC​(p.Ala38_Ala39dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,124,353 control chromosomes in the GnomAD database, including 1,267 homozygotes. There are 3,562 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (735 hom., 2048 hem., cov: 21)
  • Exomes 𝑓: 0.0066 (532 hom. 1514 hem.)
• Consequence: ATP6AP1 NM_001183.6 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.146
• 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-DT (HGNC:25138): (ATP6AP1 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001183.6
• BP6: Variant X-154428787-T-TGGCGGC is Benign according to our data. Variant chrX-154428787-T-TGGCGGC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1165872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

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.111_116dupGGCGGC	p.Ala38_Ala39dup	disruptive_inframe_insertion	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.111_116dupGGCGGC	p.Ala38_Ala39dup	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000358777.2	Q15904
	ATP6AP1	ENST00000945275.1		c.111_116dupGGCGGC	p.Ala38_Ala39dup	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000615334.1
	ATP6AP1	ENST00000862438.1		c.111_116dupGGCGGC	p.Ala38_Ala39dup	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000532497.1

Frequencies

GnomAD3 genomes AF: 0.0710 AC: 7960 AN: 112046 Hom.: 735 Cov.: 21

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.000709

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00851

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.0568

GnomAD2 exomes AF: 0.00470 AC: 256 AN: 54469 AF XY: 0.00220

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.00733

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000656

Gnomad OTH exome AF: 0.00421

GnomAD4 exome AF: 0.00662 AC: 6697 AN: 1012267 Hom.: 532 Cov.: 31 AF XY: 0.00465 AC XY: 1514 AN XY: 325735

African (AFR) AF: 0.249 AC: 5126 AN: 20599

American (AMR) AF: 0.0107 AC: 243 AN: 22637

Ashkenazi Jewish (ASJ) AF: 0.000177 AC: 3 AN: 16951

East Asian (EAS) AF: 0.000249 AC: 6 AN: 24117

South Asian (SAS) AF: 0.000498 AC: 23 AN: 46151

European-Finnish (FIN) AF: 0.0000351 AC: 1 AN: 28515

Middle Eastern (MID) AF: 0.0102 AC: 37 AN: 3620

European-Non Finnish (NFE) AF: 0.000595 AC: 480 AN: 806952

Other (OTH) AF: 0.0182 AC: 778 AN: 42725

GnomAD4 genome AF: 0.0712 AC: 7978 AN: 112086 Hom.: 735 Cov.: 21 AF XY: 0.0594 AC XY: 2048 AN XY: 34460

African (AFR) AF: 0.247 AC: 7539 AN: 30541

American (AMR) AF: 0.0270 AC: 292 AN: 10797

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.000282 AC: 1 AN: 3542

South Asian (SAS) AF: 0.000356 AC: 1 AN: 2811

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6209

Middle Eastern (MID) AF: 0.00935 AC: 2 AN: 214

European-Non Finnish (NFE) AF: 0.00107 AC: 57 AN: 53116

Other (OTH) AF: 0.0561 AC: 86 AN: 1533

Alfa AF: 0.00185 Hom.: 1

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs781797236;

hg19: chrX-153657133;

COSMIC: COSV62341026;