X-77969217-C-T

Variant names:

• chrX-77969217-C-T
• rs2077529036
• NM_001029891.3:c.422G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001029891.3(PGAM4):​c.422G>A​(p.Arg141Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 5.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAM4	NM_001029891.3	c.422G>A	p.Arg141Lys	missense_variant	Exon 1 of 1	ENST00000458128.3	NP_001025062.1
ATP7A	NM_000052.7	c.-21-2404C>T		intron_variant	Intron 1 of 22	ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.-21-2404C>T		intron_variant	Intron 1 of 21		NP_001269153.1
ATP7A	NR_104109.2	n.144-2404C>T		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAM4	ENST00000458128.3	c.422G>A	p.Arg141Lys	missense_variant	Exon 1 of 1	6	NM_001029891.3	ENSP00000412189.1
ATP7A	ENST00000341514.11	c.-21-2404C>T		intron_variant	Intron 1 of 22	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.422G>A (p.R141K) alteration is located in exon 1 (coding exon 1) of the PGAM4 gene. This alteration results from a G to A substitution at nucleotide position 422, causing the arginine (R) at amino acid position 141 to be replaced by a lysine (K). 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	0.19
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.44
Sift	Benign	0.049	D
Sift4G	Benign	0.079	T
Polyphen		0.99	D
Vest4		0.34
MutPred		0.66		Gain of ubiquitination at R141 (P = 0.0192);
MVP		0.52
MPC		1.3
ClinPred		0.98	D
GERP RS		0.12
Varity_R		0.57
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2077529036; hg19: chrX-77224714;