chrX-78013005-G-C

Variant names:

• chrX-78013005-G-C
• rs2227291
• NM_000052.7:c.2299G>C

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.2299G>C​(p.Val767Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,207,893 control chromosomes in the GnomAD database, including 20,220 homozygotes. There are 88,830 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (2588 hom., 7920 hem., cov: 22)
  • Exomes 𝑓: 0.22 (17632 hom. 80910 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 8.16
• Publications: 54 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017761588).
• BP6: Variant X-78013005-G-C is Benign according to our data. Variant chrX-78013005-G-C is described in ClinVar as Benign. ClinVar VariationId is 92382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.327 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.2299G>C	p.Val767Leu	missense	Exon 10 of 23	NP_000043.4
	ATP7A	NM_001282224.2		c.2172+1331G>C		intron	N/A	NP_001269153.1
	ATP7A	NR_104109.2		n.285-18395G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.2299G>C	p.Val767Leu	missense	Exon 10 of 23	ENSP00000345728.6
	ATP7A	ENST00000689767.1		c.2392G>C	p.Val798Leu	missense	Exon 12 of 25	ENSP00000509406.1
	ATP7A	ENST00000343533.10	TSL:5	c.2329G>C	p.Val777Leu	missense	Exon 11 of 24	ENSP00000343026.6

Frequencies

GnomAD3 genomes AF: 0.247 AC: 27258 AN: 110317 Hom.: 2591 Cov.: 22

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.227

GnomAD2 exomes AF: 0.237 AC: 43471 AN: 183436 AF XY: 0.246

Gnomad AFR exome AF: 0.327

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.278

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.217 AC: 238038 AN: 1097521 Hom.: 17632 Cov.: 32 AF XY: 0.223 AC XY: 80910 AN XY: 362935

African (AFR) AF: 0.332 AC: 8776 AN: 26395

American (AMR) AF: 0.174 AC: 6120 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 3774 AN: 19376

East Asian (EAS) AF: 0.300 AC: 9060 AN: 30195

South Asian (SAS) AF: 0.378 AC: 20469 AN: 54132

European-Finnish (FIN) AF: 0.229 AC: 9287 AN: 40532

Middle Eastern (MID) AF: 0.290 AC: 1198 AN: 4135

European-Non Finnish (NFE) AF: 0.201 AC: 168987 AN: 841477

Other (OTH) AF: 0.225 AC: 10367 AN: 46075

GnomAD4 genome AF: 0.247 AC: 27273 AN: 110372 Hom.: 2588 Cov.: 22 AF XY: 0.243 AC XY: 7920 AN XY: 32654

African (AFR) AF: 0.319 AC: 9659 AN: 30310

American (AMR) AF: 0.221 AC: 2256 AN: 10226

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 462 AN: 2640

East Asian (EAS) AF: 0.290 AC: 1019 AN: 3513

South Asian (SAS) AF: 0.346 AC: 905 AN: 2619

European-Finnish (FIN) AF: 0.215 AC: 1245 AN: 5795

Middle Eastern (MID) AF: 0.290 AC: 62 AN: 214

European-Non Finnish (NFE) AF: 0.211 AC: 11177 AN: 52882

Other (OTH) AF: 0.231 AC: 347 AN: 1503

Alfa AF: 0.218 Hom.: 5977

Bravo AF: 0.251

TwinsUK AF: 0.203 AC: 751

ALSPAC AF: 0.201 AC: 582

ESP6500AA AF: 0.329 AC: 1260

ESP6500EA AF: 0.214 AC: 1438

ExAC AF: 0.247 AC: 30043

EpiCase AF: 0.214

EpiControl AF: 0.217

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Menkes kinky-hair syndrome (2)
-	-	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	Cutis laxa, X-linked (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	X-linked distal spinal muscular atrophy type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.6	T
MutationAssessor	Benign	1.4	L
PhyloP100		8.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.023	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.25
MPC		0.83
ClinPred		0.016	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.66
Mutation Taster		=8/92	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2227291; hg19: chrX-77268502; COSMIC: COSV58444025;