rs146119866

Variant names:

• chrX-78020342-G-A
• rs146119866
• NM_000052.7:c.2725G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_000052.7(ATP7A):​c.2725G>A​(p.Ala909Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,210,170 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000034 (0 hom. 10 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.37
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29829723).
• BP6: Variant X-78020342-G-A is Benign according to our data. Variant chrX-78020342-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533670.
• BS2: High AC in GnomAdExome4 at 37 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.2725G>A	p.Ala909Thr	missense	Exon 13 of 23	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.2491G>A	p.Ala831Thr	missense	Exon 12 of 22	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.285-11058G>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.2725G>A	p.Ala909Thr	missense	Exon 13 of 23	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.2818G>A	p.Ala940Thr	missense	Exon 15 of 25	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.2755G>A	p.Ala919Thr	missense	Exon 14 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112131 Hom.: 0 Cov.: 23

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: 0.0000563

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183457 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000610

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000337 AC: 37 AN: 1098039 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 10 AN XY: 363399

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

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

European-Non Finnish (NFE) AF: 0.0000428 AC: 36 AN: 841945

Other (OTH) AF: 0.0000217 AC: 1 AN: 46089

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112131 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34281

African (AFR) AF: 0.00 AC: 0 AN: 30836

American (AMR) AF: 0.00 AC: 0 AN: 10582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 2716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6037

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53281

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	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	0.075
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.95	L
PhyloP100		2.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.25
Sift	Benign	0.48	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.85
MPC		0.22
ClinPred		0.11	T
GERP RS		5.8
Varity_R		0.25
gMVP		0.74
Mutation Taster		=95/5	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: rs146119866; hg19: chrX-77275839; COSMIC: COSV58443090;