chrX-78011681-G-A

Variant names:

• chrX-78011681-G-A
• rs782433802
• NM_000052.7:c.2172+7G>A

Variant summary

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

The NM_000052.7(ATP7A):​c.2172+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000921 in 1,086,312 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. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: ATP7A NM_000052.7 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 0 publications found

Genes affected

ATP7A (HGNC:869): (ATPase copper transporting alpha) This gene encodes a transmembrane protein that functions in copper transport across membranes. This protein is localized to the trans Golgi network, where it is predicted to supply copper to copper-dependent enzymes in the secretory pathway. It relocalizes to the plasma membrane under conditions of elevated extracellular copper, and functions in the efflux of copper from cells. Mutations in this gene are associated with Menkes disease, X-linked distal spinal muscular atrophy, and occipital horn syndrome. Alternatively-spliced transcript variants have been observed. [provided by RefSeq, Aug 2013]

PGK1 (HGNC:8896): (phosphoglycerate kinase 1) The protein encoded by this gene is a glycolytic enzyme that catalyzes the conversion of 1,3-diphosphoglycerate to 3-phosphoglycerate. The encoded protein may also act as a cofactor for polymerase alpha. Additionally, this protein is secreted by tumor cells where it participates in angiogenesis by functioning to reduce disulfide bonds in the serine protease, plasmin, which consequently leads to the release of the tumor blood vessel inhibitor angiostatin. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Deficiency of the enzyme is associated with a wide range of clinical phenotypes hemolytic anemia and neurological impairment. Pseudogenes of this gene have been defined on chromosomes 19, 21 and the X chromosome. [provided by RefSeq, Jan 2014]

PGK1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to phosphoglycerate kinase 1 deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

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 (BayesDel_noAF=-0.44).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7A	NM_000052.7	c.2172+7G>A		splice_region_variant, intron_variant	Intron 9 of 22	ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.2172+7G>A		splice_region_variant, intron_variant	Intron 9 of 21		NP_001269153.1
ATP7A	NR_104109.2	n.285-19719G>A		intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11	c.2172+7G>A		splice_region_variant, intron_variant	Intron 9 of 22	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.21e-7 AC: 1 AN: 1086312 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 352676

African (AFR) AF: 0.00 AC: 0 AN: 26184

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19297

East Asian (EAS) AF: 0.00 AC: 0 AN: 30118

South Asian (SAS) AF: 0.00 AC: 0 AN: 53778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40439

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 831469

Other (OTH) AF: 0.00 AC: 0 AN: 45724

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	10
DANN	Benign	0.74
PhyloP100		1.7

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: rs782433802; hg19: chrX-77267178;