rs2227291

chrX-78013005-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000052.7(ATP7A):c.2299G>C(p.Val767Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,207,893 control chromosomes in the GnomAD database, including 20,220 homozygotes. There are 88,830 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (2588 hom., 7920 hem., cov: 22)
  • Exomes 𝑓: 0.22 (17632 hom. 80910 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 8.16

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017761588).
• BP6: Variant X-78013005-G-C is Benign according to our data. Variant chrX-78013005-G-C is described in ClinVar as [Benign]. Clinvar id is 92382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-78013005-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7A	NM_000052.7	c.2299G>C	p.Val767Leu	missense_variant	10/23	ENST00000341514.11
ATP7A	NM_001282224.2	c.2172+1331G>C		intron_variant
ATP7A	NR_104109.2	n.285-18395G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7A	ENST00000341514.11	c.2299G>C	p.Val767Leu	missense_variant	10/23	1	NM_000052.7	P1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 27258 AN: 110317 Hom.: 2591 Cov.: 22 AF XY: 0.243 AC XY: 7907 AN XY: 32589

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.227

GnomAD3 exomes AF: 0.237 AC: 43471 AN: 183436 Hom.: 3371 AF XY: 0.246 AC XY: 16700 AN XY: 67878

Gnomad AFR exome AF: 0.327

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.278

Gnomad SAS exome AF: 0.369

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.217 AC: 238038 AN: 1097521 Hom.: 17632 Cov.: 32 AF XY: 0.223 AC XY: 80910 AN XY: 362935

Gnomad4 AFR exome AF: 0.332

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.378

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.225

GnomAD4 genome AF: 0.247 AC: 27273 AN: 110372 Hom.: 2588 Cov.: 22 AF XY: 0.243 AC XY: 7920 AN XY: 32654

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.231

Alfa AF: 0.218 Hom.: 5977

Bravo AF: 0.251

TwinsUK AF: 0.203 AC: 751

ALSPAC AF: 0.201 AC: 582

ESP6500AA AF: 0.329 AC: 1260

ESP6500EA AF: 0.214 AC: 1438

ExAC AF: 0.247 AC: 30043

EpiCase AF: 0.214

EpiControl AF: 0.217

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Menkes kinky-hair syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

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. -

X-linked distal spinal muscular atrophy type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Cutis laxa, X-linked Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.6	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.0000016	P;P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.023	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.25
MPC		0.83
ClinPred		0.016	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.66

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: rs2227291; hg19: chrX-77268502; COSMIC: COSV58444025;