chrX-77971655-T-C

Position:

• chrX-77971655-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000052.7(ATP7A):​c.14T>C​(p.Met5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M5I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11643028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7A	NM_000052.7	c.14T>C	p.Met5Thr	missense_variant	2/23	ENST00000341514.11
ATP7A	NM_001282224.2	c.14T>C	p.Met5Thr	missense_variant	2/22
ATP7A	NR_104109.2	n.178T>C		non_coding_transcript_exon_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7A	ENST00000341514.11	c.14T>C	p.Met5Thr	missense_variant	2/23	1	NM_000052.7	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 02, 2023

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 5 of the ATP7A protein (p.Met5Thr). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP7A protein function. This variant has not been reported in the literature in individuals affected with ATP7A-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	13
DANN	Benign	0.68
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.48	T;T;.;.
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.5	L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.20	N;N;.;.
REVEL	Benign	0.20
Sift	Benign	0.41	T;T;.;.
Sift4G	Benign	0.85	T;T;.;.
Polyphen		0.0	.;B;.;.
Vest4		0.34
MutPred		0.15		Gain of glycosylation at S4 (P = 0.0352);Gain of glycosylation at S4 (P = 0.0352);Gain of glycosylation at S4 (P = 0.0352);Gain of glycosylation at S4 (P = 0.0352);
MVP		0.75
MPC		0.26
ClinPred		0.050	T
GERP RS		3.0
Varity_R		0.14
gMVP		0.36

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

Other links and lift over

dbSNP: rs2077547648; hg19: chrX-77227152;