rs144655617

Variant names:

• chrX-77988612-G-A
• rs144655617
• NM_000052.7:c.491G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000052.7(ATP7A):​c.491G>A​(p.Ser164Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000689 in 1,210,047 control chromosomes in the GnomAD database, including 3 homozygotes. There are 230 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. S164C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., 96 hem., cov: 22)
  • Exomes 𝑓: 0.00043 (2 hom. 134 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.13
• Publications: 2 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004740417).
• BP6: Variant X-77988612-G-A is Benign according to our data. Variant chrX-77988612-G-A is described in ClinVar as Benign. ClinVar VariationId is 465127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 360 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.491G>A	p.Ser164Asn	missense	Exon 3 of 23	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.491G>A	p.Ser164Asn	missense	Exon 3 of 22	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.284+16851G>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.491G>A	p.Ser164Asn	missense	Exon 3 of 23	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.491G>A	p.Ser164Asn	missense	Exon 4 of 25	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.521G>A	p.Ser174Asn	missense	Exon 4 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.00322 AC: 360 AN: 111847 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000384

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00103 AC: 189 AN: 183184 AF XY: 0.000857

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000432 AC: 474 AN: 1098147 Hom.: 2 Cov.: 31 AF XY: 0.000369 AC XY: 134 AN XY: 363543

African (AFR) AF: 0.0127 AC: 336 AN: 26399

American (AMR) AF: 0.000511 AC: 18 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4137

European-Non Finnish (NFE) AF: 0.0000950 AC: 80 AN: 842057

Other (OTH) AF: 0.000759 AC: 35 AN: 46092

GnomAD4 genome AF: 0.00322 AC: 360 AN: 111900 Hom.: 1 Cov.: 22 AF XY: 0.00282 AC XY: 96 AN XY: 34084

African (AFR) AF: 0.0110 AC: 341 AN: 30883

American (AMR) AF: 0.000383 AC: 4 AN: 10435

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00 AC: 0 AN: 2706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6041

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

European-Non Finnish (NFE) AF: 0.000226 AC: 12 AN: 53190

Other (OTH) AF: 0.00197 AC: 3 AN: 1523

Alfa AF: 0.000968 Hom.: 34

Bravo AF: 0.00370

ESP6500AA AF: 0.0115 AC: 44

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.00115 AC: 140

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0047	T
MetaSVM	Uncertain	0.0087	D
MutationAssessor	Benign	1.0	L
PhyloP100		3.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.24
Sift	Benign	0.085	T
Sift4G	Uncertain	0.037	D
Polyphen		0.0	B
Vest4		0.12
MVP		0.90
MPC		0.21
ClinPred		0.0019	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.39
Mutation Taster		=95/5	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: rs144655617; hg19: chrX-77244108;