rs144655617

Variant summary

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

The NM_000052.7(ATP7A):c.491G>A(p.Ser164Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000689 in 1,210,047 control chromosomes in the GnomAD database, including 3 homozygotes. There are 230 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S164C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., 96 hem., cov: 22)

Exomes 𝑓: 0.00043 ( 2 hom. 134 hem. )

Consequence

ATP7A
NM_000052.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.13

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 (MetaRNN=0.004740417).

BP6

Variant X-77988612-G-A is Benign according to our data. Variant chrX-77988612-G-A is described in ClinVar as [Benign]. Clinvar id is 465127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-77988612-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00322 (360/111900) while in subpopulation AFR AF= 0.011 (341/30883). AF 95% confidence interval is 0.0101. There are 1 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 96 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ATP7A	NM_000052.7 linkuse as main transcript	c.491G>A	p.Ser164Asn	missense_variant	3/23	ENST00000341514.11
ATP7A	NM_001282224.2 linkuse as main transcript	c.491G>A	p.Ser164Asn	missense_variant	3/22
ATP7A	NR_104109.2 linkuse as main transcript	n.284+16851G>A		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.491G>A	p.Ser164Asn	missense_variant	3/23	1	NM_000052.7	P1	Q04656-1

Frequencies

GnomAD3 genomes

AF:

0.00322

AC:

360

AN:

111847

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

AN XY:

34019

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000384

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:

0.000226

Gnomad OTH

AF:

0.00199

GnomAD3 exomes

AF:

0.00103

AC:

189

AN:

183184

Hom.:

AF XY:

0.000857

AC XY:

AN XY:

67694

show subpopulations

Gnomad AFR exome

AF:

0.0124

Gnomad AMR exome

AF:

0.000474

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:

0.000135

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000432

AC:

474

AN:

1098147

Hom.:

Cov.:

AF XY:

0.000369

AC XY:

134

AN XY:

363543

show subpopulations

Gnomad4 AFR exome

AF:

0.0127

Gnomad4 AMR exome

AF:

0.000511

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000950

Gnomad4 OTH exome

AF:

0.000759

GnomAD4 genome

AF:

0.00322

AC:

360

AN:

111900

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

AN XY:

34084

show subpopulations

Gnomad4 AFR

AF:

0.0110

Gnomad4 AMR

AF:

0.000383

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000226

Gnomad4 OTH

AF:

0.00197

Alfa

AF:

0.000351

Hom.:

Bravo

AF:

0.00370

ESP6500AA

AF:

0.0115

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.00115

AC:

140

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2017

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. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2016

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 14, 2020

- -

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

0.075

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

Cadd

Benign

Dann

Benign

0.96

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.0047

T;T

MetaSVM

Uncertain

0.0087

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.86

N;N

REVEL

Benign

0.24

Sift

Benign

0.085

T;T

Sift4G

Uncertain

0.037

D;D

Polyphen

0.0

.;B

Vest4

0.12

MVP

0.90

MPC

0.21

ClinPred

0.0019

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.073

gMVP

0.39

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