rs143907597

Variant names:

• chrX-77998657-A-G
• rs143907597
• NM_000052.7:c.1516A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000052.7(ATP7A):​c.1516A>G​(p.Ile506Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,210,253 control chromosomes in the GnomAD database, including 20 homozygotes. There are 467 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 0.0071 (9 hom., 240 hem., cov: 23)
  • Exomes 𝑓: 0.00076 (11 hom. 227 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 9.28
• 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018511593).
• BP6: Variant X-77998657-A-G is Benign according to our data. Variant chrX-77998657-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210393.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00709 (796/112198) while in subpopulation AFR AF = 0.0248 (766/30931). AF 95% confidence interval is 0.0233. There are 9 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 796 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.1516A>G	p.Ile506Val	missense	Exon 5 of 23	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.1516A>G	p.Ile506Val	missense	Exon 5 of 22	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.284+26896A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.1516A>G	p.Ile506Val	missense	Exon 5 of 23	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.1516A>G	p.Ile506Val	missense	Exon 6 of 25	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.1546A>G	p.Ile516Val	missense	Exon 6 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.00708 AC: 794 AN: 112144 Hom.: 9 Cov.: 23

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00143

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00529

GnomAD2 exomes AF: 0.00197 AC: 360 AN: 182876 AF XY: 0.00124

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.000886

GnomAD4 exome AF: 0.000760 AC: 835 AN: 1098055 Hom.: 11 Cov.: 31 AF XY: 0.000625 AC XY: 227 AN XY: 363417

African (AFR) AF: 0.0257 AC: 678 AN: 26399

American (AMR) AF: 0.00136 AC: 48 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40493

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.0000451 AC: 38 AN: 842000

Other (OTH) AF: 0.00152 AC: 70 AN: 46090

GnomAD4 genome AF: 0.00709 AC: 796 AN: 112198 Hom.: 9 Cov.: 23 AF XY: 0.00699 AC XY: 240 AN XY: 34356

African (AFR) AF: 0.0248 AC: 766 AN: 30931

American (AMR) AF: 0.00143 AC: 15 AN: 10514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.00 AC: 0 AN: 2696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6134

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53250

Other (OTH) AF: 0.00523 AC: 8 AN: 1530

Alfa AF: 0.00253 Hom.: 117

Bravo AF: 0.00806

ESP6500AA AF: 0.0250 AC: 96

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00231 AC: 281

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	4	not specified (5)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Menkes kinky-hair syndrome (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	Benign	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.061	T
Polyphen		0.74	P
Vest4		0.50
MVP		0.96
MPC		0.76
ClinPred		0.052	T
GERP RS		5.4
Varity_R		0.34
gMVP		0.54
Mutation Taster		=51/49	polymorphism (auto)

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: rs143907597; hg19: chrX-77254154;