rs181665434

Variant names:

• chrX-78040739-T-C
• rs181665434
• NM_000052.7:c.3801+6T>C

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.3801+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 1,206,679 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 325 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., 11 hem., cov: 22)
  • Exomes 𝑓: 0.00080 (0 hom. 314 hem.)
• Consequence: ATP7A NM_000052.7 splice_region, intron
• Scores: Splicing: ADA: 0.2049
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.967
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-78040739-T-C is Benign according to our data. Variant chrX-78040739-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 56 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	NM_000052.7	MANE Select	c.3801+6T>C		splice_region intron	N/A	NP_000043.4
	ATP7A	NM_001282224.2		c.3567+6T>C		splice_region intron	N/A	NP_001269153.1
	ATP7A	NR_104109.2		n.974+6T>C		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.3801+6T>C		splice_region intron	N/A	ENSP00000345728.6
	ATP7A	ENST00000689767.1		c.3894+6T>C		splice_region intron	N/A	ENSP00000509406.1
	ATP7A	ENST00000343533.10	TSL:5	c.3831+6T>C		splice_region intron	N/A	ENSP00000343026.6

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 56 AN: 111969 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000951

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000920

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000502 AC: 92 AN: 183384 AF XY: 0.000663

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000709

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000804 AC: 880 AN: 1094656 Hom.: 0 Cov.: 30 AF XY: 0.000872 AC XY: 314 AN XY: 360210

African (AFR) AF: 0.000114 AC: 3 AN: 26328

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19361

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30177

South Asian (SAS) AF: 0.00202 AC: 109 AN: 54074

European-Finnish (FIN) AF: 0.0000988 AC: 4 AN: 40504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4060

European-Non Finnish (NFE) AF: 0.000886 AC: 743 AN: 838984

Other (OTH) AF: 0.000413 AC: 19 AN: 45965

GnomAD4 genome AF: 0.000500 AC: 56 AN: 112023 Hom.: 0 Cov.: 22 AF XY: 0.000322 AC XY: 11 AN XY: 34169

African (AFR) AF: 0.0000972 AC: 3 AN: 30875

American (AMR) AF: 0.0000950 AC: 1 AN: 10526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3589

South Asian (SAS) AF: 0.00111 AC: 3 AN: 2702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6011

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000920 AC: 49 AN: 53235

Other (OTH) AF: 0.00 AC: 0 AN: 1524

Alfa AF: 0.000800 Hom.: 5

Bravo AF: 0.000484

EpiCase AF: 0.000491

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	15
DANN	Benign	0.77
PhyloP100		0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.20
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs181665434; hg19: chrX-77296237;