rs138039591

chrX-77989631-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000052.7(ATP7A):c.1009G>A(p.Ala337Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,209,928 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 333 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., 21 hem., cov: 22)
  • Exomes 𝑓: 0.00086 (0 hom. 312 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.84

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02700618).
• BP6: Variant X-77989631-G-A is Benign according to our data. Variant chrX-77989631-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77989631-G-A is described in Lovd as [Likely_benign]. Variant chrX-77989631-G-A is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7A	NM_000052.7	c.1009G>A	p.Ala337Thr	missense_variant	4/23	ENST00000341514.11
ATP7A	NM_001282224.2	c.1009G>A	p.Ala337Thr	missense_variant	4/22
ATP7A	NR_104109.2	n.284+17870G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7A	ENST00000341514.11	c.1009G>A	p.Ala337Thr	missense_variant	4/23	1	NM_000052.7	P1

Frequencies

GnomAD3 genomes AF: 0.000671 AC: 75 AN: 111853 Hom.: 0 Cov.: 22 AF XY: 0.000617 AC XY: 21 AN XY: 34041

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000960

Gnomad OTH AF: 0.000660

GnomAD3 exomes AF: 0.000639 AC: 117 AN: 183142 Hom.: 0 AF XY: 0.000694 AC XY: 47 AN XY: 67692

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000857 AC: 941 AN: 1098022 Hom.: 0 Cov.: 31 AF XY: 0.000859 AC XY: 312 AN XY: 363418

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000653

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00120

Gnomad4 FIN exome AF: 0.000173

Gnomad4 NFE exome AF: 0.000948

Gnomad4 OTH exome AF: 0.000868

GnomAD4 genome AF: 0.000670 AC: 75 AN: 111906 Hom.: 0 Cov.: 22 AF XY: 0.000616 AC XY: 21 AN XY: 34104

Gnomad4 AFR AF: 0.000194

Gnomad4 AMR AF: 0.00153

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000371

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000960

Gnomad4 OTH AF: 0.000652

Alfa AF: 0.000962 Hom.: 45

Bravo AF: 0.000763

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000684 AC: 83

EpiCase AF: 0.000709

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2020	This variant is associated with the following publications: (PMID: 19377476) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 02, 2020

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). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	13
Dann	Benign	0.96
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Uncertain	-0.042	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.96	D;D;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.21	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.014	.;B
Vest4		0.11
MVP		0.92
MPC		0.24
ClinPred		0.025	T
GERP RS		3.9
Varity_R		0.29
gMVP		0.38

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: rs138039591; hg19: chrX-77245127;