rs138958687

Variant names:

• chrX-78021066-A-G
• rs138958687
• NM_000052.7:c.2903A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000052.7(ATP7A):​c.2903A>G​(p.Glu968Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,205,129 control chromosomes in the GnomAD database, including 1 homozygotes. There are 176 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., 22 hem., cov: 22)
  • Exomes 𝑓: 0.00042 (1 hom. 154 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:9
• Conservation: PhyloP100: 7.36
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011748552).
• BP6: Variant X-78021066-A-G is Benign according to our data. Variant chrX-78021066-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210436.
• BS2: High AC in GnomAd4 at 52 XL,AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	NM_000052.7	MANE Select	c.2903A>G	p.Glu968Gly	missense	Exon 14 of 23	NP_000043.4
	ATP7A	NM_001282224.2		c.2669A>G	p.Glu890Gly	missense	Exon 13 of 22	NP_001269153.1
	ATP7A	NR_104109.2		n.285-10334A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.2903A>G	p.Glu968Gly	missense	Exon 14 of 23	ENSP00000345728.6
	ATP7A	ENST00000689767.1		c.2996A>G	p.Glu999Gly	missense	Exon 16 of 25	ENSP00000509406.1
	ATP7A	ENST00000343533.10	TSL:5	c.2933A>G	p.Glu978Gly	missense	Exon 15 of 24	ENSP00000343026.6

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 52 AN: 111480 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000414

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000701 AC: 128 AN: 182659 AF XY: 0.000698

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000255

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00543

Gnomad NFE exome AF: 0.000305

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.000421 AC: 460 AN: 1093598 Hom.: 1 Cov.: 30 AF XY: 0.000428 AC XY: 154 AN XY: 359628

African (AFR) AF: 0.00 AC: 0 AN: 26311

American (AMR) AF: 0.000227 AC: 8 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.000465 AC: 9 AN: 19356

East Asian (EAS) AF: 0.00 AC: 0 AN: 30140

South Asian (SAS) AF: 0.000111 AC: 6 AN: 54057

European-Finnish (FIN) AF: 0.00580 AC: 230 AN: 39631

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.000223 AC: 187 AN: 838815

Other (OTH) AF: 0.000435 AC: 20 AN: 45971

GnomAD4 genome AF: 0.000466 AC: 52 AN: 111531 Hom.: 0 Cov.: 22 AF XY: 0.000652 AC XY: 22 AN XY: 33733

African (AFR) AF: 0.00 AC: 0 AN: 30685

American (AMR) AF: 0.00 AC: 0 AN: 10444

Ashkenazi Jewish (ASJ) AF: 0.000378 AC: 1 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3587

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.00490 AC: 29 AN: 5922

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

European-Non Finnish (NFE) AF: 0.000414 AC: 22 AN: 53146

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.000314 Hom.: 15

Bravo AF: 0.000219

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000725 AC: 88

EpiCase AF: 0.000218

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
1	-	1	Menkes kinky-hair syndrome (2)
-	-	1	ATP7A-related disorder (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Menkes kinky-hair syndrome;C0268353:Cutis laxa, X-linked;C1845359:X-linked distal spinal muscular atrophy type 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0084	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	0.090	N
PhyloP100		7.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.70
Sift	Benign	0.13	T
Sift4G	Benign	0.28	T
Polyphen		0.89	P
Vest4		0.24
MVP		0.93
MPC		0.57
ClinPred		0.084	T
GERP RS		5.7
Varity_R		0.37
gMVP		0.90
Mutation Taster		=87/13	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs138958687; hg19: chrX-77276563;