chrX-77969029-C-A

Variant names:

• chrX-77969029-C-A
• rs782479456
• NM_001029891.3:c.610G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001029891.3(PGAM4):​c.610G>T​(p.Ala204Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000231 in 1,210,141 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000022 (0 hom. 10 hem.)
• Consequence: PGAM4 NM_001029891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86
• Publications: 0 publications found

Genes affected

PGAM4 (HGNC:21731): (phosphoglycerate mutase family member 4) This intronless gene appears to have arisen from a retrotransposition event, yet it is thought to be an expressed, protein-coding gene. The encoded protein is a member of the phosphoglycerate mutase family, a set of enzymes that catalyze the transfer of a phosphate group from 3-phosphoglycerate to 2-phosphoglycerate. [provided by RefSeq, May 2010]

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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.094736904).
• BS2: High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAM4	NM_001029891.3	c.610G>T	p.Ala204Ser	missense_variant	Exon 1 of 1	ENST00000458128.3	NP_001025062.1
ATP7A	NM_000052.7	c.-21-2592C>A		intron_variant	Intron 1 of 22	ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.-21-2592C>A		intron_variant	Intron 1 of 21		NP_001269153.1
ATP7A	NR_104109.2	n.144-2592C>A		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAM4	ENST00000458128.3	c.610G>T	p.Ala204Ser	missense_variant	Exon 1 of 1	6	NM_001029891.3	ENSP00000412189.1
ATP7A	ENST00000341514.11	c.-21-2592C>A		intron_variant	Intron 1 of 22	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes AF: 0.0000356 AC: 4 AN: 112313 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000751

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000327 AC: 6 AN: 183409 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000733

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 24 AN: 1097774 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 10 AN XY: 363358

African (AFR) AF: 0.00 AC: 0 AN: 26384

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.000792 AC: 3 AN: 3789

European-Non Finnish (NFE) AF: 0.0000238 AC: 20 AN: 842095

Other (OTH) AF: 0.0000217 AC: 1 AN: 46061

GnomAD4 genome AF: 0.0000356 AC: 4 AN: 112367 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34529

African (AFR) AF: 0.00 AC: 0 AN: 30962

American (AMR) AF: 0.00 AC: 0 AN: 10660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6141

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

European-Non Finnish (NFE) AF: 0.0000751 AC: 4 AN: 53243

Other (OTH) AF: 0.00 AC: 0 AN: 1527

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.610G>T (p.A204S) alteration is located in exon 1 (coding exon 1) of the PGAM4 gene. This alteration results from a G to T substitution at nucleotide position 610, causing the alanine (A) at amino acid position 204 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.057	T
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.28
Sift	Benign	0.042	D
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.37		Gain of disorder (P = 0.022);
MVP		0.90
MPC		0.60
ClinPred		0.23	T
GERP RS		0.12
Varity_R		0.081
gMVP		0.68
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs782479456; hg19: chrX-77224526;