rs201999500

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000052.7(ATP7A):c.1385C>T(p.Pro462Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000736 in 1,210,000 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 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. P462A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000073 ( 0 hom. 33 hem. )

Consequence

ATP7A
NM_000052.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.379

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.094872355).

BS2

High AC in GnomAd4 at 9 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
ATP7A	NM_000052.7	MANE Select	c.1385C>T	p.Pro462Leu	missense	Exon 5 of 23	NP_000043.4
ATP7A	NM_001282224.2		c.1385C>T	p.Pro462Leu	missense	Exon 5 of 22	NP_001269153.1
ATP7A	NR_104109.2		n.284+26765C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.1385C>T	p.Pro462Leu	missense	Exon 5 of 23	ENSP00000345728.6
ATP7A	ENST00000689767.1		c.1385C>T	p.Pro462Leu	missense	Exon 6 of 25	ENSP00000509406.1
ATP7A	ENST00000343533.10	TSL:5	c.1415C>T	p.Pro472Leu	missense	Exon 6 of 24	ENSP00000343026.6

Frequencies

GnomAD3 genomes

AF:

0.0000804

AC:

AN:

111906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000650

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000327

AC:

AN:

183285

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:

0.0000612

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000729

AC:

AN:

1098094

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

363452

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26398

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:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54143

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000891

AC:

AN:

842013

Other (OTH)

AF:

0.000108

AC:

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.0000804

AC:

AN:

111906

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34086

show subpopulations

African (AFR)

AF:

0.0000650

AC:

AN:

30778

American (AMR)

AF:

0.00

AC:

AN:

10500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3588

South Asian (SAS)

AF:

0.00

AC:

AN:

2693

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

53207

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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:

0.0000968

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Inborn genetic diseases (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.34

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.095

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.20

PhyloP100

0.38

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

REVEL

Benign

0.22

Sift

Benign

0.12

Sift4G

Benign

0.11

Polyphen

0.0

Vest4

0.13

MVP

0.68

MPC

0.23

ClinPred

0.028

GERP RS

3.4

Varity_R

0.052

gMVP

0.35

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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