rs782094358

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000052.7(ATP7A):​c.2948C>T​(p.Thr983Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,209,314 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 0.000023 ( 0 hom. 6 hem. )

Consequence

ATP7A
NM_000052.7 missense

Scores

4
13

Clinical Significance

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

Conservation

PhyloP100: 2.69
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 -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12053031).
BP6
Variant X-78029281-C-T is Benign according to our data. Variant chrX-78029281-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533684.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS2
High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP7ANM_000052.7 linkuse as main transcriptc.2948C>T p.Thr983Met missense_variant 15/23 ENST00000341514.11 NP_000043.4 Q04656-1B4DRW0Q762B6
ATP7ANM_001282224.2 linkuse as main transcriptc.2714C>T p.Thr905Met missense_variant 14/22 NP_001269153.1 Q04656-5B4DRW0Q762B6
ATP7ANR_104109.2 linkuse as main transcriptn.285-2119C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP7AENST00000341514.11 linkuse as main transcriptc.2948C>T p.Thr983Met missense_variant 15/231 NM_000052.7 ENSP00000345728.6 Q04656-1

Frequencies

GnomAD3 genomes
AF:
0.0000179
AC:
2
AN:
111665
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33863
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:
0.0000376
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000273
AC:
5
AN:
183332
Hom.:
0
AF XY:
0.0000442
AC XY:
3
AN XY:
67814
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000144
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000244
Gnomad OTH exome
AF:
0.000221
GnomAD4 exome
AF:
0.0000228
AC:
25
AN:
1097649
Hom.:
0
Cov.:
31
AF XY:
0.0000165
AC XY:
6
AN XY:
363031
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000232
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000178
Gnomad4 OTH exome
AF:
0.0000434
GnomAD4 genome
AF:
0.0000179
AC:
2
AN:
111665
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33863
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:
0.0000376
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000577
AC:
7
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2021- -
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 03, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
20
DANN
Benign
0.93
DEOGEN2
Uncertain
0.47
.;T
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.47
T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Benign
0.97
.;L
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.86
N;N
REVEL
Uncertain
0.34
Sift
Benign
0.075
T;T
Sift4G
Benign
0.22
T;T
Polyphen
0.95
.;P
Vest4
0.19
MutPred
0.52
.;Loss of catalytic residue at T983 (P = 0.051);
MVP
0.82
MPC
0.30
ClinPred
0.10
T
GERP RS
1.9
Varity_R
0.031
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs782094358; hg19: chrX-77284778; COSMIC: COSV100430140; API