X-78031577-A-C

Variant names:

• chrX-78031577-A-C
• rs1557237081
• NM_000052.7:c.3289A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000341514.11(ATP7A):​c.3289A>C​(p.Lys1097Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,094,842 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic 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. K1097R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ATP7A ENST00000341514.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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]

PGK1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to phosphoglycerate kinase 1 deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000341514.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	NM_000052.7	MANE Select	c.3289A>C	p.Lys1097Gln	missense	Exon 16 of 23	NP_000043.4
	ATP7A	NM_001282224.2		c.3055A>C	p.Lys1019Gln	missense	Exon 15 of 22	NP_001269153.1
	ATP7A	NR_104109.2		n.462A>C		non_coding_transcript_exon	Exon 3 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.3289A>C	p.Lys1097Gln	missense	Exon 16 of 23	ENSP00000345728.6
	ATP7A	ENST00000689767.1		c.3382A>C	p.Lys1128Gln	missense	Exon 18 of 25	ENSP00000509406.1
	ATP7A	ENST00000343533.10	TSL:5	c.3319A>C	p.Lys1107Gln	missense	Exon 17 of 24	ENSP00000343026.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1094842 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 360396

African (AFR) AF: 0.00 AC: 0 AN: 26331

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19364

East Asian (EAS) AF: 0.00 AC: 0 AN: 30167

South Asian (SAS) AF: 0.00 AC: 0 AN: 54071

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839060

Other (OTH) AF: 0.00 AC: 0 AN: 45994

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Menkes kinky-hair syndrome;C0268353:Cutis laxa, X-linked;C1845359:X-linked distal spinal muscular atrophy type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.1	L
PhyloP100		9.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.44		Loss of methylation at K1097 (P = 0.0073)
MVP		0.98
MPC		0.65
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.55
gMVP		0.76
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs1557237081; hg19: chrX-77287075;