rs201788154

chrX-78014707-A-GchrX-78014707-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000052.7(ATP7A):c.2452A>G(p.Thr818Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00035 in 1,207,206 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 117 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T818I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., 13 hem., cov: 22)
  • Exomes 𝑓: 0.00034 (0 hom. 104 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.18

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10959506).
• BP6: Variant X-78014707-A-G is Benign according to our data. Variant chrX-78014707-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 210428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-78014707-A-G is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7A	NM_000052.7	c.2452A>G	p.Thr818Ala	missense_variant	11/23	ENST00000341514.11
ATP7A	NM_001282224.2	c.2218A>G	p.Thr740Ala	missense_variant	10/22
ATP7A	NR_104109.2	n.285-16693A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7A	ENST00000341514.11	c.2452A>G	p.Thr818Ala	missense_variant	11/23	1	NM_000052.7	P1

Frequencies

GnomAD3 genomes AF: 0.000430 AC: 48 AN: 111665 Hom.: 0 Cov.: 22 AF XY: 0.000384 AC XY: 13 AN XY: 33839

Gnomad AFR AF: 0.000260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000480

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000740

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000545

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000345 AC: 63 AN: 182615 Hom.: 0 AF XY: 0.000298 AC XY: 20 AN XY: 67131

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000221

Gnomad ASJ exome AF: 0.000668

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000538

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.000342 AC: 375 AN: 1095490 Hom.: 0 Cov.: 27 AF XY: 0.000288 AC XY: 104 AN XY: 361248

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.000207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000369

Gnomad4 OTH exome AF: 0.000587

GnomAD4 genome AF: 0.000430 AC: 48 AN: 111716 Hom.: 0 Cov.: 22 AF XY: 0.000383 AC XY: 13 AN XY: 33900

Gnomad4 AFR AF: 0.000259

Gnomad4 AMR AF: 0.000479

Gnomad4 ASJ AF: 0.000379

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000742

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000545

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000476 Hom.: 19

Bravo AF: 0.000336

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000298 AC: 2

ExAC AF: 0.000313 AC: 38

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2020	This variant is associated with the following publications: (PMID: 32818659) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	ATP7A: BS2 -

ATP7A-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2023

This alteration is classified as likely 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	23
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.64
Sift	Benign	0.12	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.97	.;D
Vest4		0.30
MVP		0.95
MPC		0.44
ClinPred		0.046	T
GERP RS		4.7
Varity_R		0.43
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs201788154; hg19: chrX-77270204;