rs200009243

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000052.7(ATP7A):c.4226+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,163,917 control chromosomes in the GnomAD database, including 68 homozygotes. There are 3,335 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 0.0047 ( 2 hom., 175 hem., cov: 23)

Exomes 𝑓: 0.0070 ( 66 hom. 3160 hem. )

Consequence

ATP7A
NM_000052.7 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.699

Variant links:

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]

ATP7A links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-78045583-T-C is Benign according to our data. Variant chrX-78045583-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 210475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-78045583-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00469 (528/112529) while in subpopulation SAS AF= 0.0365 (99/2714). AF 95% confidence interval is 0.0307. There are 2 homozygotes in gnomad4. There are 175 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
ATP7A	NM_000052.7 linkuse as main transcript	c.4226+11T>C	intron_variant	ENST00000341514.11
ATP7A	NM_001282224.2 linkuse as main transcript	c.3992+11T>C	intron_variant
ATP7A	NR_104109.2 linkuse as main transcript	n.1399+11T>C	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7A	ENST00000341514.11 linkuse as main transcript	c.4226+11T>C		intron_variant		1	NM_000052.7	P1	Q04656-1

Frequencies

GnomAD3 genomes

AF:

0.00470

AC:

529

AN:

112477

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

174

AN XY:

34629

show subpopulations

Gnomad AFR

AF:

0.000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00113

Gnomad ASJ

AF:

0.0426

Gnomad EAS

AF:

0.000276

Gnomad SAS

AF:

0.0364

Gnomad FIN

AF:

0.000326

Gnomad MID

AF:

0.0335

Gnomad NFE

AF:

0.00484

Gnomad OTH

AF:

0.00393

GnomAD3 exomes

AF:

0.00992

AC:

1808

AN:

182270

Hom.:

AF XY:

0.0140

AC XY:

940

AN XY:

67004

show subpopulations

Gnomad AFR exome

AF:

0.000760

Gnomad AMR exome

AF:

0.00215

Gnomad ASJ exome

AF:

0.0423

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.0507

Gnomad FIN exome

AF:

0.000258

Gnomad NFE exome

AF:

0.00507

Gnomad OTH exome

AF:

0.00864

GnomAD4 exome

AF:

0.00704

AC:

7405

AN:

1051388

Hom.:

Cov.:

AF XY:

0.00972

AC XY:

3160

AN XY:

325246

show subpopulations

Gnomad4 AFR exome

AF:

0.000549

Gnomad4 AMR exome

AF:

0.00213

Gnomad4 ASJ exome

AF:

0.0429

Gnomad4 EAS exome

AF:

0.000100

Gnomad4 SAS exome

AF:

0.0476

Gnomad4 FIN exome

AF:

0.000474

Gnomad4 NFE exome

AF:

0.00426

Gnomad4 OTH exome

AF:

0.00959

GnomAD4 genome

AF:

0.00469

AC:

528

AN:

112529

Hom.:

Cov.:

AF XY:

0.00504

AC XY:

175

AN XY:

34691

show subpopulations

Gnomad4 AFR

AF:

0.000966

Gnomad4 AMR

AF:

0.00113

Gnomad4 ASJ

AF:

0.0426

Gnomad4 EAS

AF:

0.000277

Gnomad4 SAS

AF:

0.0365

Gnomad4 FIN

AF:

0.000326

Gnomad4 NFE

AF:

0.00484

Gnomad4 OTH

AF:

0.00388

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.00404

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2015

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. -

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over