rs797045350

Variant names:

• chrX-78012889-G-A
• rs797045350
• NM_000052.7:c.2183G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000052.7(ATP7A):​c.2183G>A​(p.Gly728Asp) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G728R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 8.11
• Publications: 3 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000052.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant X-78012889-G-A is Pathogenic according to our data. Variant chrX-78012889-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210420.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7A	NM_000052.7	c.2183G>A	p.Gly728Asp	missense_variant	Exon 10 of 23	ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.2172+1215G>A		intron_variant	Intron 9 of 21		NP_001269153.1
ATP7A	NR_104109.2	n.285-18511G>A		intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11	c.2183G>A	p.Gly728Asp	missense_variant	Exon 10 of 23	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Menkes kinky-hair syndrome Pathogenic:1 Uncertain:2

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2022

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ATP7A related disorder (ClinVar ID: VCV000210420, PMID:21716286). It is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.929>=0.6, 3CNET: 0.794>=0.75). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		8.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.69		Loss of catalytic residue at W729 (P = 0.1112);
MVP		0.99
MPC		0.96
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.82
gMVP		0.99
Mutation Taster		=3/97	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: rs797045350; hg19: chrX-77268386;