rs5959964

Variant names:

• chrX-78014478-G-T
• rs5959964
• NM_000052.7:c.2407-184G>T

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.2407-184G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 110,528 control chromosomes in the GnomAD database, including 3,028 homozygotes. There are 8,614 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 (3028 hom., 8614 hem., cov: 22)
• Consequence: ATP7A NM_000052.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.860
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-78014478-G-T is Benign according to our data. Variant chrX-78014478-G-T is described in ClinVar as Benign. ClinVar VariationId is 254756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 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.2407-184G>T		intron	N/A	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.2173-184G>T		intron	N/A	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.285-16922G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.2407-184G>T		intron	N/A	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.2500-184G>T		intron	N/A	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.2437-184G>T		intron	N/A	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.264 AC: 29186 AN: 110477 Hom.: 3029 Cov.: 22

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.244

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.264 AC: 29205 AN: 110528 Hom.: 3028 Cov.: 22 AF XY: 0.262 AC XY: 8614 AN XY: 32868

African (AFR) AF: 0.376 AC: 11427 AN: 30406

American (AMR) AF: 0.229 AC: 2361 AN: 10326

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 466 AN: 2635

East Asian (EAS) AF: 0.259 AC: 918 AN: 3550

South Asian (SAS) AF: 0.359 AC: 947 AN: 2641

European-Finnish (FIN) AF: 0.220 AC: 1254 AN: 5710

Middle Eastern (MID) AF: 0.286 AC: 62 AN: 217

European-Non Finnish (NFE) AF: 0.213 AC: 11251 AN: 52862

Other (OTH) AF: 0.248 AC: 372 AN: 1502

Alfa AF: 0.222 Hom.: 4143

Bravo AF: 0.268

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.76
PhyloP100		-0.86
PromoterAI		-0.017	Neutral
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5959964;

hg19: chrX-77269975;