rs375788705

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_000052.7(ATP7A):ā€‹c.3863A>Gā€‹(p.Gln1288Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,210,478 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000036 ( 0 hom., 2 hem., cov: 23)
Exomes š‘“: 0.000052 ( 0 hom. 22 hem. )

Consequence

ATP7A
NM_000052.7 missense

Scores

5
5
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 9.22
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.37831873).
BP6
Variant X-78042646-A-G is Benign according to our data. Variant chrX-78042646-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234437.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
BS2
High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP7ANM_000052.7 linkuse as main transcriptc.3863A>G p.Gln1288Arg missense_variant 20/23 ENST00000341514.11 NP_000043.4
ATP7ANM_001282224.2 linkuse as main transcriptc.3629A>G p.Gln1210Arg missense_variant 19/22 NP_001269153.1
ATP7ANR_104109.2 linkuse as main transcriptn.1036A>G non_coding_transcript_exon_variant 7/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP7AENST00000341514.11 linkuse as main transcriptc.3863A>G p.Gln1288Arg missense_variant 20/231 NM_000052.7 ENSP00000345728 P1Q04656-1

Frequencies

GnomAD3 genomes
AF:
0.0000356
AC:
4
AN:
112262
Hom.:
0
Cov.:
23
AF XY:
0.0000581
AC XY:
2
AN XY:
34398
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000750
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000545
AC:
10
AN:
183446
Hom.:
0
AF XY:
0.0000295
AC XY:
2
AN XY:
67906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.000122
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000519
AC:
57
AN:
1098216
Hom.:
0
Cov.:
31
AF XY:
0.0000605
AC XY:
22
AN XY:
363574
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000665
Gnomad4 OTH exome
AF:
0.0000217
GnomAD4 genome
AF:
0.0000356
AC:
4
AN:
112262
Hom.:
0
Cov.:
23
AF XY:
0.0000581
AC XY:
2
AN XY:
34398
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000750
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000149
AC:
1
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 11, 2016The Q1288R variant in the ATP7A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Q1288R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q1288R variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret Q1288R as a variant of uncertain significance. -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2023ATP7A: BS2; PGK1: BS2 -
Menkes kinky-hair syndrome Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Apr 11, 2020- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 09, 2021This 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. -
Menkes kinky-hair syndrome;C0268353:Cutis laxa, X-linked;C1845359:X-linked distal spinal muscular atrophy type 3 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.28
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.57
.;D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Benign
0.38
T;T
MetaSVM
Uncertain
0.41
D
MutationAssessor
Benign
-0.040
.;N
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.7
N;N
REVEL
Pathogenic
0.72
Sift
Benign
0.73
T;T
Sift4G
Benign
0.38
T;T
Polyphen
0.49
.;P
Vest4
0.43
MVP
0.99
MPC
0.68
ClinPred
0.61
D
GERP RS
4.8
Varity_R
0.35
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs375788705; hg19: chrX-77298144; API