rs146651049

Positions:

• chrX-78043317-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000052.7(ATP7A):​c.4006A>G​(p.Asn1336Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000186 in 1,174,211 control chromosomes in the GnomAD database, including 1 homozygotes. There are 55 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., 26 hem., cov: 22)
  • Exomes 𝑓: 0.00012 (1 hom. 29 hem.)
• Consequence: ATP7A NM_000052.7 missense, splice_region
• Scores: Splicing: ADA: 0.03821
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.56

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015893936).
• BP6: Variant X-78043317-A-G is Benign according to our data. Variant chrX-78043317-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284224.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.
• BS2: High Hemizygotes in GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7A	NM_000052.7	c.4006A>G	p.Asn1336Asp	missense_variant, splice_region_variant	21/23	ENST00000341514.11
ATP7A	NM_001282224.2	c.3772A>G	p.Asn1258Asp	missense_variant, splice_region_variant	20/22
ATP7A	NR_104109.2	n.1179A>G		splice_region_variant, non_coding_transcript_exon_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7A	ENST00000341514.11	c.4006A>G	p.Asn1336Asp	missense_variant, splice_region_variant	21/23	1	NM_000052.7	P1

Frequencies

GnomAD3 genomes AF: 0.000801 AC: 90 AN: 112385 Hom.: 0 Cov.: 22 AF XY: 0.000753 AC XY: 26 AN XY: 34535

Gnomad AFR AF: 0.00259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000755

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: 0.00

Gnomad OTH AF: 0.00131

GnomAD3 exomes AF: 0.000268 AC: 49 AN: 182839 Hom.: 0 AF XY: 0.0000889 AC XY: 6 AN XY: 67485

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.000365

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: 0.00

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000120 AC: 127 AN: 1061772 Hom.: 1 Cov.: 24 AF XY: 0.0000869 AC XY: 29 AN XY: 333812

Gnomad4 AFR exome AF: 0.00322

Gnomad4 AMR exome AF: 0.000398

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000188

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000601

GnomAD4 genome AF: 0.000809 AC: 91 AN: 112439 Hom.: 0 Cov.: 22 AF XY: 0.000751 AC XY: 26 AN XY: 34599

Gnomad4 AFR AF: 0.00261

Gnomad4 AMR AF: 0.000754

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00129

Alfa AF: 0.000169 Hom.: 4

Bravo AF: 0.00105

ESP6500AA AF: 0.00313 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	ATP7A: BS1 -

Menkes kinky-hair syndrome;C0268353:Cutis laxa, X-linked;C1845359:X-linked distal spinal muscular atrophy type 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.016	T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	-0.65	.;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Uncertain	0.52
Sift	Benign	0.043	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.72	.;P
Vest4		0.18
MVP		0.96
MPC		0.27
ClinPred		0.061	T
GERP RS		5.2
Varity_R		0.39
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.038
dbscSNV1_RF	Benign	0.20
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: rs146651049; hg19: chrX-77298815;