rs201225704

Variant names:

• chrX-78033759-T-C
• rs201225704
• NM_000052.7:c.3449T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000052.7(ATP7A):​c.3449T>C​(p.Ile1150Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000521 in 1,209,407 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1150L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.000041 (0 hom. 13 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.63
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17810392).
• BP6: Variant X-78033759-T-C is Benign according to our data. Variant chrX-78033759-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 18 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.3449T>C	p.Ile1150Thr	missense	Exon 17 of 23	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.3215T>C	p.Ile1072Thr	missense	Exon 16 of 22	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.622T>C		non_coding_transcript_exon	Exon 4 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.3449T>C	p.Ile1150Thr	missense	Exon 17 of 23	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.3542T>C	p.Ile1181Thr	missense	Exon 19 of 25	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.3479T>C	p.Ile1160Thr	missense	Exon 18 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.000161 AC: 18 AN: 111950 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000951

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: 0.0000563

Gnomad OTH AF: 0.000661

GnomAD2 exomes AF: 0.0000873 AC: 16 AN: 183317 AF XY: 0.0000885

Gnomad AFR exome AF: 0.000532

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 45 AN: 1097405 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 13 AN XY: 362875

African (AFR) AF: 0.000493 AC: 13 AN: 26380

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30191

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54121

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3888

European-Non Finnish (NFE) AF: 0.0000285 AC: 24 AN: 841659

Other (OTH) AF: 0.000109 AC: 5 AN: 46047

GnomAD4 genome AF: 0.000161 AC: 18 AN: 112002 Hom.: 0 Cov.: 23 AF XY: 0.000176 AC XY: 6 AN XY: 34176

African (AFR) AF: 0.000422 AC: 13 AN: 30816

American (AMR) AF: 0.0000949 AC: 1 AN: 10532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3589

South Asian (SAS) AF: 0.00 AC: 0 AN: 2699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53235

Other (OTH) AF: 0.000653 AC: 1 AN: 1532

Alfa AF: 0.0000703 Hom.: 1

Bravo AF: 0.000155

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.95	L
PhyloP100		5.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.49
Sift	Benign	0.30	T
Sift4G	Benign	0.16	T
Polyphen		0.0050	B
Vest4		0.44
MVP		0.98
MPC		0.29
ClinPred		0.037	T
GERP RS		5.3
Varity_R		0.27
gMVP		0.83
Mutation Taster		=61/39	polymorphism

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: rs201225704; hg19: chrX-77289257;