X-77988438-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000052.7(ATP7A):​c.317C>T​(p.Thr106Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000711 in 1,209,690 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 0.000076 ( 0 hom. 23 hem. )

Consequence

ATP7A
NM_000052.7 missense

Scores

1
16

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.670
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 -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1337134).
BP6
Variant X-77988438-C-T is Benign according to our data. Variant chrX-77988438-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 579684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Hemizygotes in GnomAdExome4 at 23 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP7ANM_000052.7 linkuse as main transcriptc.317C>T p.Thr106Ile missense_variant 3/23 ENST00000341514.11 NP_000043.4 Q04656-1B4DRW0Q762B6
ATP7ANM_001282224.2 linkuse as main transcriptc.317C>T p.Thr106Ile missense_variant 3/22 NP_001269153.1 Q04656-5B4DRW0Q762B6
ATP7ANR_104109.2 linkuse as main transcriptn.284+16677C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP7AENST00000341514.11 linkuse as main transcriptc.317C>T p.Thr106Ile missense_variant 3/231 NM_000052.7 ENSP00000345728.6 Q04656-1

Frequencies

GnomAD3 genomes
AF:
0.0000179
AC:
2
AN:
111606
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33780
show subpopulations
Gnomad AFR
AF:
0.0000325
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:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000164
AC:
3
AN:
183328
Hom.:
0
AF XY:
0.0000147
AC XY:
1
AN XY:
67826
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000365
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:
0.0000245
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000765
AC:
84
AN:
1098084
Hom.:
0
Cov.:
31
AF XY:
0.0000633
AC XY:
23
AN XY:
363478
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000284
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:
0.0000974
Gnomad4 OTH exome
AF:
0.0000217
GnomAD4 genome
AF:
0.0000179
AC:
2
AN:
111606
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33780
show subpopulations
Gnomad4 AFR
AF:
0.0000325
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:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Menkes kinky-hair syndrome Benign:1
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Oct 28, 2019- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2023ATP7A: BP4 -
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 20, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
9.0
DANN
Benign
0.96
DEOGEN2
Benign
0.30
.;T
FATHMM_MKL
Benign
0.41
N
LIST_S2
Benign
0.65
T;T
M_CAP
Pathogenic
0.44
D
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-0.65
T
MutationAssessor
Benign
0.63
N;N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.0
N;N
REVEL
Benign
0.21
Sift
Benign
0.20
T;T
Sift4G
Benign
0.098
T;T
Polyphen
0.0
.;B
Vest4
0.17
MVP
0.72
MPC
0.24
ClinPred
0.035
T
GERP RS
3.9
Varity_R
0.19
gMVP
0.37

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: rs782647620; hg19: chrX-77243934; API