rs2234938

Variant names:

• chrX-78046457-A-G
• rs2234938
• NM_000052.7:c.4390A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000052.7(ATP7A):​c.4390A>G​(p.Ile1464Val) variant causes a missense change. The variant allele was found at a frequency of 0.00117 in 1,209,457 control chromosomes in the GnomAD database, including 27 homozygotes. There are 415 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1464K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., 26 hem., cov: 23)
  • Exomes 𝑓: 0.0012 (25 hom. 389 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.67
• Publications: 12 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=0.007471323).
• BP6: Variant X-78046457-A-G is Benign according to our data. Variant chrX-78046457-A-G is described in ClinVar as Benign. ClinVar VariationId is 166709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000996 (111/111437) while in subpopulation EAS AF = 0.0283 (100/3528). AF 95% confidence interval is 0.0238. There are 2 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 111 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.4390A>G	p.Ile1464Val	missense	Exon 23 of 23	NP_000043.4
	ATP7A	NM_001282224.2		c.4156A>G	p.Ile1386Val	missense	Exon 22 of 22	NP_001269153.1
	ATP7A	NR_104109.2		n.1563A>G		non_coding_transcript_exon	Exon 10 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.4390A>G	p.Ile1464Val	missense	Exon 23 of 23	ENSP00000345728.6
	ATP7A	ENST00000689767.1		c.4483A>G	p.Ile1495Val	missense	Exon 25 of 25	ENSP00000509406.1
	ATP7A	ENST00000343533.10	TSL:5	c.4420A>G	p.Ile1474Val	missense	Exon 24 of 24	ENSP00000343026.6

Frequencies

GnomAD3 genomes AF: 0.000988 AC: 110 AN: 111382 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0000980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.000761

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00264

GnomAD2 exomes AF: 0.00136 AC: 249 AN: 183415 AF XY: 0.000958

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00243

GnomAD4 exome AF: 0.00118 AC: 1300 AN: 1098020 Hom.: 25 Cov.: 31 AF XY: 0.00107 AC XY: 389 AN XY: 363380

African (AFR) AF: 0.0000379 AC: 1 AN: 26397

American (AMR) AF: 0.000114 AC: 4 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.0392 AC: 1184 AN: 30202

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000202 AC: 17 AN: 841932

Other (OTH) AF: 0.00195 AC: 90 AN: 46091

GnomAD4 genome AF: 0.000996 AC: 111 AN: 111437 Hom.: 2 Cov.: 23 AF XY: 0.000773 AC XY: 26 AN XY: 33621

African (AFR) AF: 0.0000978 AC: 3 AN: 30673

American (AMR) AF: 0.0000954 AC: 1 AN: 10483

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.0283 AC: 100 AN: 3528

South Asian (SAS) AF: 0.000764 AC: 2 AN: 2618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53077

Other (OTH) AF: 0.00261 AC: 4 AN: 1533

Alfa AF: 0.000811 Hom.: 19

Bravo AF: 0.000790

ExAC AF: 0.00112 AC: 136

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Menkes kinky-hair syndrome;C0268353:Cutis laxa, X-linked;C1845359:X-linked distal spinal muscular atrophy type 3 (3)
-	-	3	not specified (3)
-	-	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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.20
Sift	Benign	0.046	D
Sift4G	Benign	0.33	T
Polyphen		0.88	P
Vest4		0.14
MVP		0.90
MPC		0.20
ClinPred		0.029	T
GERP RS		4.9
Varity_R		0.18
gMVP		0.19
Mutation Taster		=97/3	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: rs2234938; hg19: chrX-77301954;