rs944415019

Variant names:

• chrX-78011573-G-A
• rs944415019
• NM_000052.7:c.2071G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000052.7(ATP7A):​c.2071G>A​(p.Glu691Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000909 in 1,209,582 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000091 (0 hom. 3 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.46
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant X-78011573-G-A is Benign according to our data. Variant chrX-78011573-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465109.
• BS2: High AC in GnomAdExome4 at 10 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.2071G>A	p.Glu691Lys	missense	Exon 9 of 23	NP_000043.4
	ATP7A	NM_001282224.2		c.2071G>A	p.Glu691Lys	missense	Exon 9 of 22	NP_001269153.1
	ATP7A	NR_104109.2		n.285-19827G>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.2071G>A	p.Glu691Lys	missense	Exon 9 of 23	ENSP00000345728.6
	ATP7A	ENST00000689767.1		c.2164G>A	p.Glu722Lys	missense	Exon 11 of 25	ENSP00000509406.1
	ATP7A	ENST00000343533.10	TSL:5	c.2101G>A	p.Glu701Lys	missense	Exon 10 of 24	ENSP00000343026.6

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111683 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1097899 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 3 AN XY: 363345

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.00 AC: 0 AN: 35203

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30161

South Asian (SAS) AF: 0.00 AC: 0 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40481

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841923

Other (OTH) AF: 0.00 AC: 0 AN: 46083

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111683 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33841

African (AFR) AF: 0.00 AC: 0 AN: 30771

American (AMR) AF: 0.00 AC: 0 AN: 10408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3602

South Asian (SAS) AF: 0.00 AC: 0 AN: 2674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5963

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53187

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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	0.11
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.3	L
PhyloP100		6.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.54
Sift	Benign	0.048	D
Sift4G	Benign	0.77	T
Polyphen		0.91	P
Vest4		0.63
MutPred		0.38		Gain of ubiquitination at E691 (P = 0.0131)
MVP		0.89
MPC		0.39
ClinPred		0.90	D
GERP RS		4.8
Varity_R		0.41
gMVP		0.75
Mutation Taster		=56/44	polymorphism

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: rs944415019; hg19: chrX-77267070;