chrX-78015774-A-C

Variant names:

• chrX-78015774-A-C
• rs372318616
• NM_000052.7:c.2519A>C

Variant summary

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

The NM_000052.7(ATP7A):​c.2519A>C​(p.Glu840Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,787 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E840V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.08
• 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000052.7. 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
	ATP7A	NM_000052.7	MANE Select	c.2519A>C	p.Glu840Ala	missense	Exon 12 of 23	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.2285A>C	p.Glu762Ala	missense	Exon 11 of 22	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.285-15626A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.2519A>C	p.Glu840Ala	missense	Exon 12 of 23	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.2612A>C	p.Glu871Ala	missense	Exon 14 of 25	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.2549A>C	p.Glu850Ala	missense	Exon 13 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097787 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363177

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30184

South Asian (SAS) AF: 0.00 AC: 0 AN: 54134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841770

Other (OTH) AF: 0.00 AC: 0 AN: 46077

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.1	L
PhyloP100		9.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.95	P
Vest4		0.50
MutPred		0.60		Loss of disorder (P = 0.0969)
MVP		0.95
MPC		0.83
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.64
gMVP		0.80
Mutation Taster		=64/36	polymorphism

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: rs372318616; hg19: chrX-77271271;