NM_001029891.3:c.169A>G

Variant names:

• chrX-77969470-T-C
• NM_001029891.3:c.169A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001029891.3(PGAM4):​c.169A>G​(p.Thr57Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PGAM4 NM_001029891.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59
• 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: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029891.3. 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
	PGAM4	NM_001029891.3	MANE Select	c.169A>G	p.Thr57Ala	missense	Exon 1 of 1	NP_001025062.1	Q8N0Y7
	ATP7A	NM_000052.7	MANE Select	c.-21-2151T>C		intron	N/A	NP_000043.4	Q04656-1
	ATP7A	NM_001282224.2		c.-21-2151T>C		intron	N/A	NP_001269153.1	Q04656-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAM4	ENST00000458128.3	TSL:6 MANE Select	c.169A>G	p.Thr57Ala	missense	Exon 1 of 1	ENSP00000412189.1	Q8N0Y7
	ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.-21-2151T>C		intron	N/A	ENSP00000345728.6	Q04656-1
	ATP7A	ENST00000689767.1		c.-21-2151T>C		intron	N/A	ENSP00000509406.1	A0A8I5KWA8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.95	P
Vest4		0.69
MutPred		0.85		Loss of catalytic residue at T57 (P = 0.1322)
MVP		0.55
MPC		0.80
ClinPred		0.99	D
GERP RS		0.12
PromoterAI		-0.023	Neutral
Varity_R		0.63
gMVP		0.92
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

hg19: chrX-77224967;