rs113968994

Variant names:

• chrX-78020916-C-A
• rs113968994
• NM_000052.7:c.2782-29C>A

Variant summary

Our verdict is Benign. The variant received -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
• 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 254757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000052.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	NM_000052.7	MANE Select	c.2782-29C>A		intron	N/A	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.2548-29C>A		intron	N/A	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.285-10484C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.2782-29C>A		intron	N/A	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.2875-29C>A		intron	N/A	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.2812-29C>A		intron	N/A	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.257 AC: 28249 AN: 109776 Hom.: 2897 Cov.: 21

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

GnomAD2 exomes AF: 0.245 AC: 44593 AN: 181721 AF XY: 0.252

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 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

African (AFR) AF: 0.356 AC: 9117 AN: 25603

American (AMR) AF: 0.184 AC: 6445 AN: 35114

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 3794 AN: 19182

East Asian (EAS) AF: 0.299 AC: 8950 AN: 29939

South Asian (SAS) AF: 0.378 AC: 20161 AN: 53298

European-Finnish (FIN) AF: 0.235 AC: 9277 AN: 39419

Middle Eastern (MID) AF: 0.293 AC: 1172 AN: 3999

European-Non Finnish (NFE) AF: 0.208 AC: 170121 AN: 817729

Other (OTH) AF: 0.233 AC: 10543 AN: 45159

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

African (AFR) AF: 0.340 AC: 10224 AN: 30108

American (AMR) AF: 0.227 AC: 2325 AN: 10248

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 468 AN: 2621

East Asian (EAS) AF: 0.288 AC: 1003 AN: 3483

South Asian (SAS) AF: 0.338 AC: 866 AN: 2559

European-Finnish (FIN) AF: 0.209 AC: 1189 AN: 5701

Middle Eastern (MID) AF: 0.282 AC: 60 AN: 213

European-Non Finnish (NFE) AF: 0.220 AC: 11622 AN: 52742

Other (OTH) AF: 0.247 AC: 367 AN: 1483

Alfa AF: 0.229 Hom.: 4944

Bravo AF: 0.267

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.11
DANN	Benign	0.20
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs113968994; hg19: chrX-77276413; COSMIC: COSV107408298;