rs2228447

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000052.7(ATP7A):c.565A>G(p.Ile189Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,209,342 control chromosomes in the GnomAD database, including 21 homozygotes. There are 445 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 9 hom., 218 hem., cov: 22)

Exomes 𝑓: 0.00077 ( 12 hom. 227 hem. )

Consequence

ATP7A
NM_000052.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 8.95

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01656577).

BP6

Variant X-77988686-A-G is Benign according to our data. Variant chrX-77988686-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 210477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77988686-A-G is described in Lovd as [Benign]. Variant chrX-77988686-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00695 (775/111542) while in subpopulation AFR AF= 0.0243 (746/30739). AF 95% confidence interval is 0.0228. There are 9 homozygotes in gnomad4. There are 218 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7A	NM_000052.7 link	c.565A>G	p.Ile189Val	missense_variant	Exon 3 of 23	ENST00000341514.11	NP_000043.4	Q04656-1B4DRW0Q762B6
ATP7A	NM_001282224.2 link	c.565A>G	p.Ile189Val	missense_variant	Exon 3 of 22		NP_001269153.1	Q04656-5B4DRW0Q762B6
ATP7A	NR_104109.2 link	n.284+16925A>G		intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11 link	c.565A>G	p.Ile189Val	missense_variant	Exon 3 of 23	1	NM_000052.7	ENSP00000345728.6		Q04656-1

Frequencies

GnomAD3 genomes

AF:

0.00692

AC:

772

AN:

111489

Hom.:

Cov.:

AF XY:

0.00645

AC XY:

217

AN XY:

33669

show subpopulations

Gnomad AFR

AF:

0.0242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00532

GnomAD3 exomes

AF:

0.00198

AC:

361

AN:

182195

Hom.:

AF XY:

0.00126

AC XY:

AN XY:

67207

show subpopulations

Gnomad AFR exome

AF:

0.0248

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000247

Gnomad OTH exome

AF:

0.000889

GnomAD4 exome

AF:

0.000765

AC:

840

AN:

1097800

Hom.:

Cov.:

AF XY:

0.000625

AC XY:

227

AN XY:

363240

show subpopulations

Gnomad4 AFR exome

AF:

0.0258

Gnomad4 AMR exome

AF:

0.00136

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:

0.0000451

Gnomad4 OTH exome

AF:

0.00152

GnomAD4 genome

AF:

0.00695

AC:

775

AN:

111542

Hom.:

Cov.:

AF XY:

0.00646

AC XY:

218

AN XY:

33732

show subpopulations

Gnomad4 AFR

AF:

0.0243

Gnomad4 AMR

AF:

0.00134

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.00525

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.00808

ESP6500AA

AF:

0.0250

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.00231

AC:

281

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 18, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Benign:3

Jul 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 04, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Ehlers-Danlos syndrome

Benign:1

Jul 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

-0.0075

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.61

N;N

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.052

T;D

Polyphen

0.42

.;B

Vest4

0.35

MVP

0.97

MPC

0.43

ClinPred

0.061

GERP RS

5.1

Varity_R

0.30

gMVP

0.75

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