X-78011498-G-A

Variant names:

• chrX-78011498-G-A
• rs797045344
• NM_000052.7:c.1996G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Very_Strong PM2 PP3_Moderate PP5_Moderate

The NM_000052.7(ATP7A):​c.1996G>A​(p.Gly666Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.11

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS1: Transcript NM_000052.7 (ATP7A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 210411
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant X-78011498-G-A is Pathogenic according to our data. Variant chrX-78011498-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210410.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7A	NM_000052.7	c.1996G>A	p.Gly666Arg	missense_variant	Exon 9 of 23	ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.1996G>A	p.Gly666Arg	missense_variant	Exon 9 of 22		NP_001269153.1
ATP7A	NR_104109.2	n.285-19902G>A		intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11	c.1996G>A	p.Gly666Arg	missense_variant	Exon 9 of 23	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Menkes kinky-hair syndrome Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.92
Sift	Benign	0.35	T;D
Sift4G	Benign	0.10	T;T
Polyphen		0.99	.;D
Vest4		0.81
MutPred		0.68		Gain of methylation at G666 (P = 0.0244);Gain of methylation at G666 (P = 0.0244);
MVP		1.0
MPC		0.81
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.78
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045344; hg19: chrX-77266995;