rs781892236

Positions:

• chrX-78015836-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000052.7(ATP7A):​c.2581C>T​(p.Arg861Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,209,578 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. 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. R861H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000029 (0 hom. 13 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant X-78015836-C-T is Benign according to our data. Variant chrX-78015836-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 465114.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7A	NM_000052.7	c.2581C>T	p.Arg861Cys	missense_variant	12/23	ENST00000341514.11
ATP7A	NM_001282224.2	c.2347C>T	p.Arg783Cys	missense_variant	11/22
ATP7A	NR_104109.2	n.285-15564C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7A	ENST00000341514.11	c.2581C>T	p.Arg861Cys	missense_variant	12/23	1	NM_000052.7	P1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111966 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34158

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000164 AC: 3 AN: 183362 Hom.: 0 AF XY: 0.0000295 AC XY: 2 AN XY: 67832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000292 AC: 32 AN: 1097612 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 13 AN XY: 363010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.0000741

Gnomad4 NFE exome AF: 0.0000285

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111966 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34158

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Menkes kinky-hair syndrome;C0268353:Cutis laxa, X-linked;C1845359:X-linked distal spinal muscular atrophy type 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Uncertain	0.70	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	.;D
Vest4		0.42
MutPred		0.65		.;Loss of methylation at R861 (P = 0.0285);
MVP		1.0
MPC		0.36
ClinPred		0.67	D
GERP RS		4.5
Varity_R		0.35
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs781892236; hg19: chrX-77271333;