NM_000052.7:c.1955G>A

Variant names:

• chrX-78011457-G-A
• rs143214563
• NM_000052.7:c.1955G>A

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.1955G>A​(p.Arg652Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,206,180 control chromosomes in the GnomAD database, including 1 homozygotes. There are 68 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. R652W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., 24 hem., cov: 22)
  • Exomes 𝑓: 0.00015 (1 hom. 44 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 3.09
• Publications: 4 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016769081).
• BP6: Variant X-78011457-G-A is Benign according to our data. Variant chrX-78011457-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284222.
• BS2: High AC in GnomAd4 at 96 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	NM_000052.7	MANE Select	c.1955G>A	p.Arg652Gln	missense	Exon 9 of 23	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.1955G>A	p.Arg652Gln	missense	Exon 9 of 22	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.285-19943G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.1955G>A	p.Arg652Gln	missense	Exon 9 of 23	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.2048G>A	p.Arg683Gln	missense	Exon 11 of 25	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.1985G>A	p.Arg662Gln	missense	Exon 10 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.000858 AC: 95 AN: 110739 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000775

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000756

Gnomad OTH AF: 0.00135

GnomAD2 exomes AF: 0.000328 AC: 60 AN: 183134 AF XY: 0.000133

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000489

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000147 AC: 161 AN: 1095389 Hom.: 1 Cov.: 30 AF XY: 0.000122 AC XY: 44 AN XY: 360961

African (AFR) AF: 0.00326 AC: 86 AN: 26356

American (AMR) AF: 0.000398 AC: 14 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.0000995 AC: 3 AN: 30157

South Asian (SAS) AF: 0.000148 AC: 8 AN: 54059

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40382

Middle Eastern (MID) AF: 0.000485 AC: 2 AN: 4126

European-Non Finnish (NFE) AF: 0.0000238 AC: 20 AN: 839734

Other (OTH) AF: 0.000609 AC: 28 AN: 46012

GnomAD4 genome AF: 0.000866 AC: 96 AN: 110791 Hom.: 0 Cov.: 22 AF XY: 0.000726 AC XY: 24 AN XY: 33079

African (AFR) AF: 0.00269 AC: 82 AN: 30532

American (AMR) AF: 0.000774 AC: 8 AN: 10339

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.00 AC: 0 AN: 2590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000756 AC: 4 AN: 52931

Other (OTH) AF: 0.00133 AC: 2 AN: 1505

Alfa AF: 0.000307 Hom.: 11

Bravo AF: 0.00110

ESP6500AA AF: 0.00339 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.29
Sift	Benign	0.33	T
Sift4G	Benign	0.33	T
Polyphen		0.47	P
Vest4		0.24
MVP		0.90
MPC		0.26
ClinPred		0.019	T
GERP RS		4.8
Varity_R		0.20
gMVP		0.50
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143214563; hg19: chrX-77266954;