rs150526992

Variant names:

• chrX-77989502-A-T
• rs150526992
• NM_000052.7:c.880A>T

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.880A>T​(p.Asn294Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,210,214 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 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 0.00059 (0 hom., 17 hem., cov: 23)
  • Exomes 𝑓: 0.000056 (0 hom. 16 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 5.26
• Publications: 1 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=0.031488925).
• BP6: Variant X-77989502-A-T is Benign according to our data. Variant chrX-77989502-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533685.
• BS2: High AC in GnomAd4 at 66 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.880A>T	p.Asn294Tyr	missense	Exon 4 of 23	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.880A>T	p.Asn294Tyr	missense	Exon 4 of 22	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.284+17741A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.880A>T	p.Asn294Tyr	missense	Exon 4 of 23	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.880A>T	p.Asn294Tyr	missense	Exon 5 of 25	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.910A>T	p.Asn304Tyr	missense	Exon 5 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.000588 AC: 66 AN: 112203 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000949

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000169 AC: 31 AN: 183081 AF XY: 0.0000739

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000556 AC: 61 AN: 1097955 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 16 AN XY: 363359

African (AFR) AF: 0.00189 AC: 50 AN: 26392

American (AMR) AF: 0.000114 AC: 4 AN: 35207

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841895

Other (OTH) AF: 0.000108 AC: 5 AN: 46091

GnomAD4 genome AF: 0.000588 AC: 66 AN: 112259 Hom.: 0 Cov.: 23 AF XY: 0.000494 AC XY: 17 AN XY: 34445

African (AFR) AF: 0.00207 AC: 64 AN: 30991

American (AMR) AF: 0.0000948 AC: 1 AN: 10547

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3595

South Asian (SAS) AF: 0.00 AC: 0 AN: 2726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6139

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

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53166

Other (OTH) AF: 0.00 AC: 0 AN: 1537

Alfa AF: 0.000101 Hom.: 2

Bravo AF: 0.000555

ESP6500AA AF: 0.00209 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	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	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.42
MVP		0.94
MPC		0.92
ClinPred		0.17	T
GERP RS		4.2
Varity_R		0.39
gMVP		0.86
Mutation Taster		=50/50

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: rs150526992; hg19: chrX-77244998;