rs113968994

Positions:

• chrX-78020916-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000052.7(ATP7A):​c.2782-29C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,179,271 control chromosomes in the GnomAD database, including 21,567 homozygotes. There are 87,731 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (2895 hom., 7791 hem., cov: 21)
  • Exomes 𝑓: 0.22 (18672 hom. 79940 hem.)
• Consequence: ATP7A NM_000052.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.932

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-78020916-C-A is Benign according to our data. Variant chrX-78020916-C-A is described in ClinVar as [Benign]. Clinvar id is 254757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-78020916-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7A	NM_000052.7	c.2782-29C>A		intron_variant		ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.2548-29C>A		intron_variant			NP_001269153.1
ATP7A	NR_104109.2	n.285-10484C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11	c.2782-29C>A		intron_variant		1	NM_000052.7	ENSP00000345728	P1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 28249 AN: 109776 Hom.: 2897 Cov.: 21 AF XY: 0.242 AC XY: 7774 AN XY: 32106

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.244

GnomAD3 exomes AF: 0.245 AC: 44593 AN: 181721 Hom.: 3629 AF XY: 0.252 AC XY: 16808 AN XY: 66587

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.277

Gnomad SAS exome AF: 0.369

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.230

GnomAD4 exome AF: 0.224 AC: 239580 AN: 1069442 Hom.: 18672 Cov.: 28 AF XY: 0.229 AC XY: 79940 AN XY: 348630

Gnomad4 AFR exome AF: 0.356

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.299

Gnomad4 SAS exome AF: 0.378

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.208

Gnomad4 OTH exome AF: 0.233

GnomAD4 genome AF: 0.257 AC: 28267 AN: 109829 Hom.: 2895 Cov.: 21 AF XY: 0.242 AC XY: 7791 AN XY: 32171

Gnomad4 AFR AF: 0.340

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.288

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.247

Alfa AF: 0.234 Hom.: 3298

Bravo AF: 0.267

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 10, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.11
DANN	Benign	0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113968994; hg19: chrX-77276413;