dbSNP rs142521666: ATP7A:p.Cys288Cys (chrX-77989486-T-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000052.7(ATP7A):c.864T>C(p.Cys288Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,210,151 control chromosomes in the GnomAD database, including 1 homozygotes. There are 138 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., 18 hem., cov: 22)

Exomes 𝑓: 0.00034 ( 1 hom. 120 hem. )

Consequence

ATP7A
NM_000052.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.93

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

glycogen storage disease due to phosphoglycerate kinase 1 deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

PGK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant X-77989486-T-C is Benign according to our data. Variant chrX-77989486-T-C is described in ClinVar as Benign. ClinVar VariationId is 533682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.93 with no splicing effect.

BS2

High AC in GnomAd4 at 52 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000052.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP7A	NM_000052.7	MANE Select	c.864T>C	p.Cys288Cys	synonymous	Exon 4 of 23	NP_000043.4	Q04656-1
ATP7A	NM_001282224.2		c.864T>C	p.Cys288Cys	synonymous	Exon 4 of 22	NP_001269153.1	Q04656-5
ATP7A	NR_104109.2		n.284+17725T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.864T>C	p.Cys288Cys	synonymous	Exon 4 of 23	ENSP00000345728.6	Q04656-1
ATP7A	ENST00000689767.1		c.864T>C	p.Cys288Cys	synonymous	Exon 5 of 25	ENSP00000509406.1	A0A8I5KWA8
ATP7A	ENST00000343533.10	TSL:5	c.894T>C	p.Cys298Cys	synonymous	Exon 5 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes

AF:

0.000455

AC:

AN:

112101

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0139

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000657

GnomAD2 exomes

AF:

0.00152

AC:

279

AN:

183062

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0197

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000886

GnomAD4 exome

AF:

0.000336

AC:

369

AN:

1097994

Hom.:

Cov.:

AF XY:

0.000330

AC XY:

120

AN XY:

363400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.0115

AC:

347

AN:

30198

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40527

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000713

AC:

AN:

841922

Other (OTH)

AF:

0.000282

AC:

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000464

AC:

AN:

112157

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

34347

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30940

American (AMR)

AF:

0.00

AC:

AN:

10537

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.0142

AC:

AN:

3585

South Asian (SAS)

AF:

0.00

AC:

AN:

2723

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53183

Other (OTH)

AF:

0.000649

AC:

AN:

1541

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000117

Hom.:

Bravo

AF:

0.000782

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ehlers-Danlos syndrome (1)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

8.1

(source)

DANN

Benign

0.58

PhyloP100

1.9

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over