rs782351352

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000052.7(ATP7A):ā€‹c.922A>Gā€‹(p.Ile308Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,210,244 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 61 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000071 ( 0 hom., 1 hem., cov: 23)
Exomes š‘“: 0.00016 ( 0 hom. 60 hem. )

Consequence

ATP7A
NM_000052.7 missense

Scores

1
16

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.843
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 Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04033476).
BP6
Variant X-77989544-A-G is Benign according to our data. Variant chrX-77989544-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 243111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Hemizygotes in GnomAdExome4 at 60 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP7ANM_000052.7 linkuse as main transcriptc.922A>G p.Ile308Val missense_variant 4/23 ENST00000341514.11 NP_000043.4 Q04656-1B4DRW0Q762B6
ATP7ANM_001282224.2 linkuse as main transcriptc.922A>G p.Ile308Val missense_variant 4/22 NP_001269153.1 Q04656-5B4DRW0Q762B6
ATP7ANR_104109.2 linkuse as main transcriptn.284+17783A>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP7AENST00000341514.11 linkuse as main transcriptc.922A>G p.Ile308Val missense_variant 4/231 NM_000052.7 ENSP00000345728.6 Q04656-1

Frequencies

GnomAD3 genomes
AF:
0.0000713
AC:
8
AN:
112254
Hom.:
0
Cov.:
23
AF XY:
0.0000291
AC XY:
1
AN XY:
34412
show subpopulations
Gnomad AFR
AF:
0.0000323
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:
0.000113
Gnomad OTH
AF:
0.000657
GnomAD3 exomes
AF:
0.0000873
AC:
16
AN:
183211
Hom.:
0
AF XY:
0.000103
AC XY:
7
AN XY:
67739
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000182
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:
0.000135
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000158
AC:
174
AN:
1097990
Hom.:
0
Cov.:
31
AF XY:
0.000165
AC XY:
60
AN XY:
363398
show subpopulations
Gnomad4 AFR exome
AF:
0.0000379
Gnomad4 AMR exome
AF:
0.000114
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:
0.000196
Gnomad4 OTH exome
AF:
0.0000868
GnomAD4 genome
AF:
0.0000713
AC:
8
AN:
112254
Hom.:
0
Cov.:
23
AF XY:
0.0000291
AC XY:
1
AN XY:
34412
show subpopulations
Gnomad4 AFR
AF:
0.0000323
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:
0.000113
Gnomad4 OTH
AF:
0.000657
Bravo
AF:
0.0000680
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.000218
EpiControl
AF:
0.000237

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024ATP7A: BP4, BS2 -
Likely benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2018- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 18, 2022This 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 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.056
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
0.57
DANN
Benign
0.76
DEOGEN2
Benign
0.35
.;T
FATHMM_MKL
Benign
0.062
N
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.040
T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
-0.38
N;N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.22
N;N
REVEL
Benign
0.14
Sift
Benign
0.44
T;T
Sift4G
Benign
0.74
T;T
Polyphen
0.0010
.;B
Vest4
0.049
MutPred
0.41
Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP
0.65
MPC
0.19
ClinPred
0.025
T
GERP RS
-1.7
Varity_R
0.070
gMVP
0.26

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs782351352; hg19: chrX-77245040; API