X-78015774-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP4_Strong BP6 BS2

The NM_000052.7(ATP7A):​c.2519A>T​(p.Glu840Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,209,903 control chromosomes in the GnomAD database, including 2 homozygotes. There are 67 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 0.00019 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00016 (2 hom. 62 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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: Benign. The variant received -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.046560407).
• BP6: Variant X-78015774-A-T is Benign according to our data. Variant chrX-78015774-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465113.
• BS2: High AC in GnomAd4 at 21 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.2519A>T	p.Glu840Val	missense	Exon 12 of 23	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.2285A>T	p.Glu762Val	missense	Exon 11 of 22	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.285-15626A>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.2519A>T	p.Glu840Val	missense	Exon 12 of 23	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.2612A>T	p.Glu871Val	missense	Exon 14 of 25	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.2549A>T	p.Glu850Val	missense	Exon 13 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.000187 AC: 21 AN: 112116 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00680

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000563

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000300 AC: 55 AN: 183354 AF XY: 0.000265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00588

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000165 AC: 181 AN: 1097787 Hom.: 2 Cov.: 30 AF XY: 0.000171 AC XY: 62 AN XY: 363177

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

American (AMR) AF: 0.0000284 AC: 1 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00712 AC: 138 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: 0.0000297 AC: 25 AN: 841770

Other (OTH) AF: 0.000369 AC: 17 AN: 46077

GnomAD4 genome AF: 0.000187 AC: 21 AN: 112116 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34276

African (AFR) AF: 0.00 AC: 0 AN: 30806

American (AMR) AF: 0.00 AC: 0 AN: 10549

Ashkenazi Jewish (ASJ) AF: 0.00680 AC: 18 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6133

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53256

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.000654 Hom.: 4

Bravo AF: 0.000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.047	T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.69	P
Vest4		0.61
MVP		0.97
MPC		0.89
ClinPred		0.16	T
GERP RS		5.3
Varity_R		0.71
gMVP		0.81
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;