X-78042666-C-T

Variant names:

• chrX-78042666-C-T
• rs372489000
• NM_000052.7:c.3883C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000052.7(ATP7A):​c.3883C>T​(p.Arg1295Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000442 in 1,209,953 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 182 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00047 (0 hom. 177 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 2.06

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07134363).
• BP6: Variant X-78042666-C-T is Benign according to our data. Variant chrX-78042666-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 245875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7A	NM_000052.7	c.3883C>T	p.Arg1295Trp	missense_variant	Exon 20 of 23	ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.3649C>T	p.Arg1217Trp	missense_variant	Exon 19 of 22		NP_001269153.1
ATP7A	NR_104109.2	n.1056C>T		non_coding_transcript_exon_variant	Exon 7 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7A	ENST00000341514.11	c.3883C>T	p.Arg1295Trp	missense_variant	Exon 20 of 23	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes AF: 0.000188 AC: 21 AN: 111747 Hom.: 0 Cov.: 23 AF XY: 0.000147 AC XY: 5 AN XY: 33937

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.000756

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000244

Gnomad OTH AF: 0.000666

GnomAD3 exomes AF: 0.000185 AC: 34 AN: 183431 Hom.: 0 AF XY: 0.000191 AC XY: 13 AN XY: 67899

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.000943

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000468 AC: 514 AN: 1098154 Hom.: 0 Cov.: 31 AF XY: 0.000487 AC XY: 177 AN XY: 363512

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000443

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000566

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000188 AC: 21 AN: 111799 Hom.: 0 Cov.: 23 AF XY: 0.000147 AC XY: 5 AN XY: 33999

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000280

Gnomad4 SAS AF: 0.000758

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000244

Gnomad4 OTH AF: 0.000657

Alfa AF: 0.000344 Hom.: 1

Bravo AF: 0.000147

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Menkes kinky-hair syndrome Uncertain:1

Jan 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jun 15, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ATP7A-related disorder Benign:1

Apr 01, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Oct 05, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33151932) -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.071	T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.27	.;B
Vest4		0.19
MVP		0.86
MPC		0.24
ClinPred		0.23	T
GERP RS		4.0
Varity_R		0.38
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs372489000; hg19: chrX-77298164; COSMIC: COSV58445561; COSMIC: COSV58445561;