rs61747968

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000052.7(ATP7A):c.327G>A(p.Lys109Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,209,712 control chromosomes in the GnomAD database, including 89 homozygotes. There are 5,038 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0097 ( 9 hom., 275 hem., cov: 22)

Exomes 𝑓: 0.013 ( 80 hom. 4763 hem. )

Consequence

ATP7A
NM_000052.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.15

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

glycogen storage disease due to phosphoglycerate kinase 1 deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

PGK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant X-77988448-G-A is Benign according to our data. Variant chrX-77988448-G-A is described in ClinVar as Benign. ClinVar VariationId is 287259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.15 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00968 (1080/111603) while in subpopulation NFE AF = 0.0162 (859/53094). AF 95% confidence interval is 0.0153. There are 9 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 1080 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7A	NM_000052.7 link	c.327G>A	p.Lys109Lys	synonymous_variant	Exon 3 of 23	ENST00000341514.11	NP_000043.4	Q04656-1B4DRW0Q762B6
ATP7A	NM_001282224.2 link	c.327G>A	p.Lys109Lys	synonymous_variant	Exon 3 of 22		NP_001269153.1	Q04656-5B4DRW0Q762B6
ATP7A	NR_104109.2 link	n.284+16687G>A		intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11 link	c.327G>A	p.Lys109Lys	synonymous_variant	Exon 3 of 23	1	NM_000052.7	ENSP00000345728.6		Q04656-1

Frequencies

GnomAD3 genomes

AF:

0.00968

AC:

1080

AN:

111551

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00625

Gnomad ASJ

AF:

0.00679

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00261

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.00531

GnomAD2 exomes

AF:

0.0101

AC:

1858

AN:

183336

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.00190

Gnomad AMR exome

AF:

0.00222

Gnomad ASJ exome

AF:

0.00614

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0167

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0134

AC:

14687

AN:

1098109

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

4763

AN XY:

363505

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

26398

American (AMR)

AF:

0.00256

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00562

AC:

109

AN:

19381

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00327

AC:

177

AN:

54134

European-Finnish (FIN)

AF:

0.0155

AC:

628

AN:

40527

Middle Eastern (MID)

AF:

0.00266

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0156

AC:

13129

AN:

842030

Other (OTH)

AF:

0.0111

AC:

513

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

634

1268

1901

2535

3169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

468

936

1404

1872

2340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00968

AC:

1080

AN:

111603

Hom.:

Cov.:

AF XY:

0.00813

AC XY:

275

AN XY:

33805

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

30777

American (AMR)

AF:

0.00624

AC:

AN:

10412

Ashkenazi Jewish (ASJ)

AF:

0.00679

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3567

South Asian (SAS)

AF:

0.00262

AC:

AN:

2673

European-Finnish (FIN)

AF:

0.0117

AC:

AN:

5996

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0162

AC:

859

AN:

53094

Other (OTH)

AF:

0.00524

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0125

Hom.:

Bravo

AF:

0.00837

EpiCase

AF:

0.0129

EpiControl

AF:

0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 31, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:2

Feb 03, 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

- -

Inborn genetic diseases

Benign:1

Jun 10, 2014

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

Jun 17, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ATP7A-related disorder

Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

5.3

(source)

DANN

Benign

0.61

PhyloP100

2.1

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over