rs61747968

Variant names:

• chrX-77988448-G-A
• rs61747968
• NM_000052.7:c.327G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000052.7(ATP7A):​c.327G>A​(p.Lys109Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,209,712 control chromosomes in the GnomAD database, including 89 homozygotes. There are 5,038 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (9 hom., 275 hem., cov: 22)
  • Exomes 𝑓: 0.013 (80 hom. 4763 hem.)
• Consequence: ATP7A NM_000052.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.15
• 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, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant X-77988448-G-A is Benign according to our data. Variant chrX-77988448-G-A is described in ClinVar as Benign. ClinVar VariationId is 287259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00968 (1080/111603) while in subpopulation NFE AF = 0.0162 (859/53094). AF 95% confidence interval is 0.0153. There are 9 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1080 XL,AD gene.

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.327G>A	p.Lys109Lys	synonymous	Exon 3 of 23	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.327G>A	p.Lys109Lys	synonymous	Exon 3 of 22	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.284+16687G>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.327G>A	p.Lys109Lys	synonymous	Exon 3 of 23	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.327G>A	p.Lys109Lys	synonymous	Exon 4 of 25	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.357G>A	p.Lys119Lys	synonymous	Exon 4 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.00968 AC: 1080 AN: 111551 Hom.: 9 Cov.: 22

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00625

Gnomad ASJ AF: 0.00679

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00261

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.00531

GnomAD2 exomes AF: 0.0101 AC: 1858 AN: 183336 AF XY: 0.0104

Gnomad AFR exome AF: 0.00190

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.00614

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0134 AC: 14687 AN: 1098109 Hom.: 80 Cov.: 31 AF XY: 0.0131 AC XY: 4763 AN XY: 363505

African (AFR) AF: 0.00114 AC: 30 AN: 26398

American (AMR) AF: 0.00256 AC: 90 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00562 AC: 109 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00327 AC: 177 AN: 54134

European-Finnish (FIN) AF: 0.0155 AC: 628 AN: 40527

Middle Eastern (MID) AF: 0.00266 AC: 11 AN: 4137

European-Non Finnish (NFE) AF: 0.0156 AC: 13129 AN: 842030

Other (OTH) AF: 0.0111 AC: 513 AN: 46091

GnomAD4 genome AF: 0.00968 AC: 1080 AN: 111603 Hom.: 9 Cov.: 22 AF XY: 0.00813 AC XY: 275 AN XY: 33805

African (AFR) AF: 0.00166 AC: 51 AN: 30777

American (AMR) AF: 0.00624 AC: 65 AN: 10412

Ashkenazi Jewish (ASJ) AF: 0.00679 AC: 18 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.00262 AC: 7 AN: 2673

European-Finnish (FIN) AF: 0.0117 AC: 70 AN: 5996

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.0162 AC: 859 AN: 53094

Other (OTH) AF: 0.00524 AC: 8 AN: 1527

Alfa AF: 0.0125 Hom.: 95

Bravo AF: 0.00837

EpiCase AF: 0.0129

EpiControl AF: 0.0138

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Menkes kinky-hair syndrome;C0268353:Cutis laxa, X-linked;C1845359:X-linked distal spinal muscular atrophy type 3 (2)
-	-	2	not provided (2)
-	-	1	ATP7A-related disorder (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.3
DANN	Benign	0.61
PhyloP100		2.1
Mutation Taster		=89/11	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: rs61747968; hg19: chrX-77243944;