X-77968926-G-A

Variant names:

• chrX-77968926-G-A
• rs1482832333
• NM_001029891.3:c.713C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001029891.3(PGAM4):​c.713C>T​(p.Thr238Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000108 in 1,208,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 2 hem.)
• Consequence: PGAM4 NM_001029891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16
• Publications: 1 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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAM4	NM_001029891.3	c.713C>T	p.Thr238Met	missense_variant	Exon 1 of 1	ENST00000458128.3	NP_001025062.1
ATP7A	NM_000052.7	c.-21-2695G>A		intron_variant	Intron 1 of 22	ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.-21-2695G>A		intron_variant	Intron 1 of 21		NP_001269153.1
ATP7A	NR_104109.2	n.144-2695G>A		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAM4	ENST00000458128.3	c.713C>T	p.Thr238Met	missense_variant	Exon 1 of 1	6	NM_001029891.3	ENSP00000412189.1
ATP7A	ENST00000341514.11	c.-21-2695G>A		intron_variant	Intron 1 of 22	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111849 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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183322 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: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1096865 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 2 AN XY: 363143

African (AFR) AF: 0.0000379 AC: 1 AN: 26358

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19385

East Asian (EAS) AF: 0.000132 AC: 4 AN: 30206

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54093

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2967

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 842134

Other (OTH) AF: 0.00 AC: 0 AN: 45982

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111849 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34011

African (AFR) AF: 0.00 AC: 0 AN: 30776

American (AMR) AF: 0.00 AC: 0 AN: 10579

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2695

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6027

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53157

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.713C>T (p.T238M) alteration is located in exon 1 (coding exon 1) of the PGAM4 gene. This alteration results from a C to T substitution at nucleotide position 713, causing the threonine (T) at amino acid position 238 to be replaced by a methionine (M). 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	0.079
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.43
MutPred		0.39		Gain of catalytic residue at T238 (P = 0.0014);
MVP		0.99
MPC		0.53
ClinPred		0.43	T
GERP RS		-0.24
Varity_R		0.20
gMVP		0.84
Mutation Taster		=90/10	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: rs1482832333; hg19: chrX-77224423; COSMIC: COSV58446534; COSMIC: COSV58446534;