NM_000052.7:c.2452A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 7.18

Publications

4 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

PGK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 210428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 48 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000052.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP7A	NM_000052.7	MANE Select	c.2452A>G	p.Thr818Ala	missense	Exon 11 of 23	NP_000043.4	Q04656-1
ATP7A	NM_001282224.2		c.2218A>G	p.Thr740Ala	missense	Exon 10 of 22	NP_001269153.1	Q04656-5
ATP7A	NR_104109.2		n.285-16693A>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.2452A>G	p.Thr818Ala	missense	Exon 11 of 23	ENSP00000345728.6	Q04656-1
ATP7A	ENST00000689767.1		c.2545A>G	p.Thr849Ala	missense	Exon 13 of 25	ENSP00000509406.1	A0A8I5KWA8
ATP7A	ENST00000343533.10	TSL:5	c.2482A>G	p.Thr828Ala	missense	Exon 12 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes

AF:

0.000430

AC:

AN:

111665

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000345

AC:

AN:

182615

AF XY:

0.000298

show subpopulations

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 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.:

Cov.:

AF XY:

0.000288

AC XY:

104

AN XY:

361248

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

26348

American (AMR)

AF:

0.000256

AC:

AN:

35161

Ashkenazi Jewish (ASJ)

AF:

0.000207

AC:

AN:

19325

East Asian (EAS)

AF:

0.00

AC:

AN:

30041

South Asian (SAS)

AF:

0.000148

AC:

AN:

53924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40491

Middle Eastern (MID)

AF:

0.00291

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.000369

AC:

310

AN:

840075

Other (OTH)

AF:

0.000587

AC:

AN:

45999

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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

100

<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:

0.000430

AC:

AN:

111716

Hom.:

Cov.:

AF XY:

0.000383

AC XY:

AN XY:

33900

show subpopulations

African (AFR)

AF:

0.000259

AC:

AN:

30832

American (AMR)

AF:

0.000479

AC:

AN:

10433

Ashkenazi Jewish (ASJ)

AF:

0.000379

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3568

South Asian (SAS)

AF:

0.000742

AC:

AN:

2696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5946

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000545

AC:

AN:

53188

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000461

Hom.:

Bravo

AF:

0.000336

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000298

AC:

ExAC

AF:

0.000313

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

ATP7A-related disorder (1)

Inborn genetic diseases (1)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.11

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

0.030

PhyloP100

7.2

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.64

Sift

Benign

0.12

Sift4G

Benign

0.24

Polyphen

0.97

Vest4

0.30

MVP

0.95

MPC

0.44

ClinPred

0.046

GERP RS

4.7

PromoterAI

0.038

Neutral

(source)

Varity_R

0.43

gMVP

0.70

Mutation Taster

=70/30

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over