rs72554644

chrX-78012885-G-AchrX-78012885-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000052.7(ATP7A):c.2179G>A(p.Gly727Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,681 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G727E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 10.0

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 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000052.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-78012886-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1685249.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant X-78012885-G-A is Pathogenic according to our data. Variant chrX-78012885-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 210418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-78012885-G-A is described in Lovd as [Pathogenic]. Variant chrX-78012885-G-A is described in Lovd as [Pathogenic]. Variant chrX-78012885-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7A	NM_000052.7	c.2179G>A	p.Gly727Arg	missense_variant	10/23	ENST00000341514.11
ATP7A	NM_001282224.2	c.2172+1211G>A		intron_variant
ATP7A	NR_104109.2	n.285-18515G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7A	ENST00000341514.11	c.2179G>A	p.Gly727Arg	missense_variant	10/23	1	NM_000052.7	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095681 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 361179

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Menkes kinky-hair syndrome Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2021

The c.2179G>A (p.G727R) alteration is located in exon 10 (coding exon 9) of the ATP7A gene. This alteration results from a G to A substitution at nucleotide position 2179, causing the glycine (G) at amino acid position 727 to be replaced by an arginine (R). This mutation was identified in three males with Menkes disease (Tang, 2008). This mutation was also observed in a female with severe intellectual disability, short fine hair, a large fontanelle, hypotonia, dry skin with hypopigmentation, increased copper uptake and retention in fibroblasts, and a family history of a severely affected brother; she had a normal karyotype and skewed X inactivation (Møller, 2012). Internal structural analysis indicates that this alteration is more disruptive than a general cutoff for pathogenic variants (Gourdon, 2011). Western blot and RT-PCR analysis from patient fibroblasts demonstrated normal transcript levels, decreased protein levels, and increased protein degradation compared to wild type (Tang, 2008) Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2023

Published functional studies demonstrate a damaging effect with protein instability and degradation, and hampered copper-induced trafficking (Tang et al., 2008; Skjrringe et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28397151, 30618512, 26582918, 24882692, 7977350, 21208200, 28389643, 22264391, 20652413, 25428120, 18752978, 27535533, 34430447, 33894639, 34390520) -

Menkes kinky-hair syndrome;C0268353:Cutis laxa, X-linked;C1845359:X-linked distal spinal muscular atrophy type 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 07, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects ATP7A function (PMID: 18752978, 28389643). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP7A protein function. ClinVar contains an entry for this variant (Variation ID: 210418). This missense change has been observed in individual(s) with ATP7A-related copper transport disorders (PMID: 18752978, 28389643, 28397151). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 727 of the ATP7A protein (p.Gly727Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.71		Gain of methylation at G727 (P = 0.0126);
MVP		1.0
MPC		0.92
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.65
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs72554644; hg19: chrX-77268382;