rs539177302

Positions:

• chrX-77988399-C-G
• chrX-77988399-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000052.7(ATP7A):​c.278C>G​(p.Thr93Arg) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.38

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]

ATP7A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-77988399-C-G is Benign according to our data. Variant chrX-77988399-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 387402.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7A	NM_000052.7	c.278C>G	p.Thr93Arg	missense_variant	3/23	ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.278C>G	p.Thr93Arg	missense_variant	3/22		NP_001269153.1
ATP7A	NR_104109.2	n.284+16638C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11	c.278C>G	p.Thr93Arg	missense_variant	3/23	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Menkes kinky-hair syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 27, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 09, 2017

The T93R variant in the ATP7A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T93R variant was not observed in approximately 6,500 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 T93R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that c.278C>G (aka T93R) might create a cryptic acceptor site in exon 3 which may supplant the natural donor site. However, in the absence of RNA/functional studies, the actual effect of c.278C>G in this individual is unknown.We interpret T93R as a variant of uncertain significance. -

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 submitter

clinical testing

3billion

Sep 20, 2024

The hemizygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the hemizygous variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Benign	0.53
DEOGEN2	Benign	0.36	.;T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.068	D
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.58	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.46	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.28	.;B
Vest4		0.37
MutPred		0.51		Loss of catalytic residue at V92 (P = 0.1985);Loss of catalytic residue at V92 (P = 0.1985);
MVP		0.91
MPC		0.31
ClinPred		0.16	T
GERP RS		2.9
Varity_R		0.089
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.52		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs539177302; hg19: chrX-77243895;