X-78042666-C-T

Position:

chrX-78042666-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000052.7(ATP7A):c.3883C>T(p.Arg1295Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000442 in 1,209,953 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 182 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.00047 ( 0 hom. 177 hem. )

Consequence

ATP7A
NM_000052.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:4

Conservation

PhyloP100: 2.06

Variant links:

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]

ATP7A links:

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]

PGK1 links:

ATP7A (HGNC:):

ATP7A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07134363).

BP6

Variant X-78042666-C-T is Benign according to our data. Variant chrX-78042666-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 245875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7A	NM_000052.7 linkuse as main transcript	c.3883C>T	p.Arg1295Trp	missense_variant	20/23	ENST00000341514.11	NP_000043.4	Q04656-1B4DRW0Q762B6
ATP7A	NM_001282224.2 linkuse as main transcript	c.3649C>T	p.Arg1217Trp	missense_variant	19/22		NP_001269153.1	Q04656-5B4DRW0Q762B6
ATP7A	NR_104109.2 linkuse as main transcript	n.1056C>T		non_coding_transcript_exon_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11 linkuse as main transcript	c.3883C>T	p.Arg1295Trp	missense_variant	20/23	1	NM_000052.7	ENSP00000345728.6		Q04656-1

Frequencies

GnomAD3 genomes

AF:

0.000188

AC:

AN:

111747

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

AN XY:

33937

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.000756

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000244

Gnomad OTH

AF:

0.000666

GnomAD3 exomes

AF:

0.000185

AC:

AN:

183431

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

67899

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.000943

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000468

AC:

514

AN:

1098154

Hom.:

Cov.:

AF XY:

0.000487

AC XY:

177

AN XY:

363512

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000443

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000566

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000188

AC:

AN:

111799

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

AN XY:

33999

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000280

Gnomad4 SAS

AF:

0.000758

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000244

Gnomad4 OTH

AF:

0.000657

Alfa

AF:

0.000344

Hom.:

Bravo

AF:

0.000147

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Menkes kinky-hair syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 24, 2020

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2017

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. -

ATP7A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2021

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 provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2020

This variant is associated with the following publications: (PMID: 33151932) -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;D

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.071

T;T

MetaSVM

Uncertain

0.55

MutationAssessor

Uncertain

2.6

.;M

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.27

.;B

Vest4

0.19

MVP

0.86

MPC

0.24

ClinPred

0.23

GERP RS

4.0

Varity_R

0.38

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over