rs61742278

Variant names:

• chrX-78009217-A-G
• rs61742278
• NM_000052.7:c.1823A>G
• ATP7A p.Tyr608Cys

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000052.7(ATP7A):​c.1823A>G​(p.Tyr608Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,208,330 control chromosomes in the GnomAD database, including 2 homozygotes. There are 198 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 0.0036 (0 hom., 100 hem., cov: 22)
  • Exomes 𝑓: 0.00038 (2 hom. 98 hem.)
• Consequence: ATP7A NM_000052.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.45
• Publications: 1 publications found

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]

PGK1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to phosphoglycerate kinase 1 deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017039835).
• BP6: Variant X-78009217-A-G is Benign according to our data. Variant chrX-78009217-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 394 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	NM_000052.7	MANE Select	c.1823A>G	p.Tyr608Cys	missense	Exon 7 of 23	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.1823A>G	p.Tyr608Cys	missense	Exon 7 of 22	NP_001269153.1	Q04656-5
	ATP7A	NR_104109.2		n.285-22183A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.1823A>G	p.Tyr608Cys	missense	Exon 7 of 23	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.1916A>G	p.Tyr639Cys	missense	Exon 9 of 25	ENSP00000509406.1	A0A8I5KWA8
	ATP7A	ENST00000343533.10	TSL:5	c.1853A>G	p.Tyr618Cys	missense	Exon 8 of 24	ENSP00000343026.6	A0A8J9FM07

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 393 AN: 110853 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00145

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000767

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.00268

GnomAD2 exomes AF: 0.00105 AC: 193 AN: 183481 AF XY: 0.000677

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000378 AC: 415 AN: 1097424 Hom.: 2 Cov.: 31 AF XY: 0.000270 AC XY: 98 AN XY: 362808

African (AFR) AF: 0.0125 AC: 329 AN: 26384

American (AMR) AF: 0.000682 AC: 24 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 841378

Other (OTH) AF: 0.00126 AC: 58 AN: 46073

GnomAD4 genome AF: 0.00355 AC: 394 AN: 110906 Hom.: 0 Cov.: 22 AF XY: 0.00302 AC XY: 100 AN XY: 33098

African (AFR) AF: 0.0122 AC: 372 AN: 30529

American (AMR) AF: 0.00145 AC: 15 AN: 10345

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.000385 AC: 1 AN: 2599

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52975

Other (OTH) AF: 0.00264 AC: 4 AN: 1513

Alfa AF: 0.00116 Hom.: 57

Bravo AF: 0.00421

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Menkes kinky-hair syndrome;C0268353:Cutis laxa, X-linked;C1845359:X-linked distal spinal muscular atrophy type 3 (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		2.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.51
gMVP		0.94
Mutation Taster		=60/40	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61742278;

hg19: chrX-77264714;