rs782774219

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000052.7(ATP7A):c.4424A>G(p.Asn1475Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000728 in 1,209,098 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1475K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000077 ( 0 hom. 26 hem. )

Consequence

ATP7A
NM_000052.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2O:1

Conservation

PhyloP100: 3.45

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15747073).

BP6

Variant X-78046491-A-G is Benign according to our data. Variant chrX-78046491-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521337.

BS2

High AC in GnomAdExome4 at 85 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7A	NM_000052.7 link	c.4424A>G	p.Asn1475Ser	missense_variant	Exon 23 of 23	ENST00000341514.11	NP_000043.4	Q04656-1B4DRW0Q762B6
ATP7A	NM_001282224.2 link	c.4190A>G	p.Asn1397Ser	missense_variant	Exon 22 of 22		NP_001269153.1	Q04656-5B4DRW0Q762B6
ATP7A	NR_104109.2 link	n.1597A>G		non_coding_transcript_exon_variant	Exon 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11 link	c.4424A>G	p.Asn1475Ser	missense_variant	Exon 23 of 23	1	NM_000052.7	ENSP00000345728.6		Q04656-1

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

111212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183298

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000774

AC:

AN:

1097886

Hom.:

Cov.:

AF XY:

0.0000716

AC XY:

AN XY:

363248

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26389

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000962

AC:

AN:

841808

Other (OTH)

AF:

0.0000651

AC:

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000270

AC:

AN:

111212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33402

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30552

American (AMR)

AF:

0.00

AC:

AN:

10403

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3543

South Asian (SAS)

AF:

0.00

AC:

AN:

2631

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

53032

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Benign:1Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 11-21-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Sep 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Menkes kinky-hair syndrome

Uncertain:1

Jul 17, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1

Sep 15, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign in association with a connective tissue disorder to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33151932) -

Inborn genetic diseases

Benign:1

Jan 02, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

.;T

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.29

.;N

PhyloP100

3.4

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.10

Sift

Benign

0.15

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.0090

.;B

Vest4

0.20

MutPred

0.13

.;Gain of phosphorylation at N1475 (P = 0.0056);

MVP

0.74

MPC

0.19

ClinPred

0.11

GERP RS

2.6

Varity_R

0.11

gMVP

0.16

Mutation Taster

=80/20

polymorphism

(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