X-77988399-C-T

Variant names:

• chrX-77988399-C-T
• rs539177302
• NM_000052.7:c.278C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000052.7(ATP7A):​c.278C>T​(p.Thr93Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 1,209,709 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T93R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.000027 (0 hom. 9 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.38
• Publications: 4 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1516687).
• BP6: Variant X-77988399-C-T is Benign according to our data. Variant chrX-77988399-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372700.
• BS2: High AC in GnomAd4 at 14 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	NM_000052.7	MANE Select	c.278C>T	p.Thr93Met	missense	Exon 3 of 23	NP_000043.4
	ATP7A	NM_001282224.2		c.278C>T	p.Thr93Met	missense	Exon 3 of 22	NP_001269153.1
	ATP7A	NR_104109.2		n.284+16638C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.278C>T	p.Thr93Met	missense	Exon 3 of 23	ENSP00000345728.6
	ATP7A	ENST00000689767.1		c.278C>T	p.Thr93Met	missense	Exon 4 of 25	ENSP00000509406.1
	ATP7A	ENST00000343533.10	TSL:5	c.308C>T	p.Thr103Met	missense	Exon 4 of 24	ENSP00000343026.6

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 14 AN: 111732 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000670

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.000664

GnomAD2 exomes AF: 0.0000382 AC: 7 AN: 183129 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000273 AC: 30 AN: 1097925 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 9 AN XY: 363323

African (AFR) AF: 0.0000379 AC: 1 AN: 26398

American (AMR) AF: 0.000170 AC: 6 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19366

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000249 AC: 21 AN: 841901

Other (OTH) AF: 0.0000434 AC: 2 AN: 46085

GnomAD4 genome AF: 0.000125 AC: 14 AN: 111784 Hom.: 0 Cov.: 22 AF XY: 0.000177 AC XY: 6 AN XY: 33970

African (AFR) AF: 0.0000324 AC: 1 AN: 30849

American (AMR) AF: 0.000669 AC: 7 AN: 10461

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.000279 AC: 1 AN: 3581

South Asian (SAS) AF: 0.000375 AC: 1 AN: 2667

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6027

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53118

Other (OTH) AF: 0.000655 AC: 1 AN: 1526

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.90	L
PhyloP100		1.4
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T
Sift4G	Benign	0.093	T
Polyphen		0.75	P
Vest4		0.28
MVP		0.88
MPC		0.31
ClinPred		0.034	T
GERP RS		2.9
Varity_R		0.029
gMVP		0.57
Mutation Taster		=94/6	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: rs539177302; hg19: chrX-77243895; COSMIC: COSV58446048;