chrX-78048530-T-C

Variant names:

• chrX-78048530-T-C
• rs1062472
• NM_000052.7:c.*1960T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000052.7(ATP7A):​c.*1960T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 110,589 control chromosomes in the GnomAD database, including 10,795 homozygotes. There are 14,325 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.45 (10788 hom., 14297 hem., cov: 22)
  • Exomes 𝑓: 0.27 (7 hom. 28 hem.)
• Consequence: ATP7A NM_000052.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.963
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7A	NM_000052.7	c.*1960T>C		3_prime_UTR_variant	Exon 23 of 23	ENST00000341514.11	NP_000043.4
ATP7A	NR_104109.2	n.3636T>C		non_coding_transcript_exon_variant	Exon 10 of 10
ATP7A	NM_001282224.2	c.*1960T>C		3_prime_UTR_variant	Exon 22 of 22		NP_001269153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11	c.*1960T>C		3_prime_UTR_variant	Exon 23 of 23	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes AF: 0.449 AC: 49524 AN: 110239 Hom.: 10779 Cov.: 22

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.399

GnomAD4 exome AF: 0.272 AC: 81 AN: 298 Hom.: 7 Cov.: 0 AF XY: 0.222 AC XY: 28 AN XY: 126

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.273 AC: 80 AN: 293

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.333 AC: 1 AN: 3

GnomAD4 genome AF: 0.450 AC: 49593 AN: 110291 Hom.: 10788 Cov.: 22 AF XY: 0.439 AC XY: 14297 AN XY: 32549

African (AFR) AF: 0.859 AC: 25954 AN: 30203

American (AMR) AF: 0.344 AC: 3550 AN: 10326

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 660 AN: 2634

East Asian (EAS) AF: 0.381 AC: 1323 AN: 3474

South Asian (SAS) AF: 0.466 AC: 1214 AN: 2603

European-Finnish (FIN) AF: 0.279 AC: 1624 AN: 5815

Middle Eastern (MID) AF: 0.419 AC: 90 AN: 215

European-Non Finnish (NFE) AF: 0.273 AC: 14432 AN: 52846

Other (OTH) AF: 0.400 AC: 599 AN: 1496

Alfa AF: 0.309 Hom.: 5765

Bravo AF: 0.469

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.063
DANN	Benign	0.47
PhyloP100		-0.96
Mutation Taster		=100/0	polymorphism (auto)

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: rs1062472; hg19: chrX-77304027; COSMIC: COSV58456273;