rs143214563

Positions:

• chrX-78011457-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000052.7(ATP7A):​c.1955G>A​(p.Arg652Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,206,180 control chromosomes in the GnomAD database, including 1 homozygotes. There are 68 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.00087 (0 hom., 24 hem., cov: 22)
  • Exomes 𝑓: 0.00015 (1 hom. 44 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.09

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]

ATP7A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016769081).
• BP6: Variant X-78011457-G-A is Benign according to our data. Variant chrX-78011457-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284222.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chrX-78011457-G-A is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7A	NM_000052.7	c.1955G>A	p.Arg652Gln	missense_variant	9/23	ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.1955G>A	p.Arg652Gln	missense_variant	9/22		NP_001269153.1
ATP7A	NR_104109.2	n.285-19943G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11	c.1955G>A	p.Arg652Gln	missense_variant	9/23	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes AF: 0.000858 AC: 95 AN: 110739 Hom.: 0 Cov.: 22 AF XY: 0.000727 AC XY: 24 AN XY: 33017

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000775

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: 0.0000756

Gnomad OTH AF: 0.00135

GnomAD3 exomes AF: 0.000328 AC: 60 AN: 183134 Hom.: 0 AF XY: 0.000133 AC XY: 9 AN XY: 67692

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000489

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000147 AC: 161 AN: 1095389 Hom.: 1 Cov.: 30 AF XY: 0.000122 AC XY: 44 AN XY: 360961

Gnomad4 AFR exome AF: 0.00326

Gnomad4 AMR exome AF: 0.000398

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000995

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000238

Gnomad4 OTH exome AF: 0.000609

GnomAD4 genome AF: 0.000866 AC: 96 AN: 110791 Hom.: 0 Cov.: 22 AF XY: 0.000726 AC XY: 24 AN XY: 33079

Gnomad4 AFR AF: 0.00269

Gnomad4 AMR AF: 0.000774

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000756

Gnomad4 OTH AF: 0.00133

Alfa AF: 0.000152 Hom.: 6

Bravo AF: 0.00110

ESP6500AA AF: 0.00339 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000321 AC: 39

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	ATP7A: BS1 -

Menkes kinky-hair syndrome;C0268353:Cutis laxa, X-linked;C1845359:X-linked distal spinal muscular atrophy type 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.017	T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.33	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.47	.;P
Vest4		0.24
MVP		0.90
MPC		0.26
ClinPred		0.019	T
GERP RS		4.8
Varity_R		0.20
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143214563; hg19: chrX-77266954;