chrX-77969382-C-T

Variant names:

• chrX-77969382-C-T
• rs62621209
• NM_001029891.3:c.257G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001029891.3(PGAM4):​c.257G>A​(p.Arg86His) variant causes a missense change. The variant allele was found at a frequency of 0.0557 in 1,205,949 control chromosomes in the GnomAD database, including 1,571 homozygotes. There are 20,050 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R86S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.041 (119 hom., 1124 hem., cov: 22)
  • Exomes 𝑓: 0.057 (1452 hom. 18926 hem.)
• Consequence: PGAM4 NM_001029891.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.51
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02993089).
• BP6: Variant X-77969382-C-T is Benign according to our data. Variant chrX-77969382-C-T is described in ClinVar as [Benign]. Clinvar id is 804036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.064 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAM4	NM_001029891.3	c.257G>A	p.Arg86His	missense_variant	Exon 1 of 1	ENST00000458128.3	NP_001025062.1
ATP7A	NM_000052.7	c.-21-2239C>T		intron_variant	Intron 1 of 22	ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2	c.-21-2239C>T		intron_variant	Intron 1 of 21		NP_001269153.1
ATP7A	NR_104109.2	n.144-2239C>T		intron_variant	Intron 1 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAM4	ENST00000458128.3	c.257G>A	p.Arg86His	missense_variant	Exon 1 of 1	6	NM_001029891.3	ENSP00000412189.1
ATP7A	ENST00000341514.11	c.-21-2239C>T		intron_variant	Intron 1 of 22	1	NM_000052.7	ENSP00000345728.6

Frequencies

GnomAD3 genomes AF: 0.0411 AC: 4590 AN: 111584 Hom.: 119 Cov.: 22

Gnomad AFR AF: 0.00812

Gnomad AMI AF: 0.0734

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0598

Gnomad EAS AF: 0.000564

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.0339

Gnomad NFE AF: 0.0658

Gnomad OTH AF: 0.0420

GnomAD2 exomes AF: 0.0441 AC: 7986 AN: 181003 AF XY: 0.0431

Gnomad AFR exome AF: 0.00740

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0631

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0488

Gnomad NFE exome AF: 0.0684

Gnomad OTH exome AF: 0.0520

GnomAD4 exome AF: 0.0572 AC: 62627 AN: 1094312 Hom.: 1452 Cov.: 32 AF XY: 0.0525 AC XY: 18926 AN XY: 360550

African (AFR) AF: 0.00744 AC: 196 AN: 26350

American (AMR) AF: 0.0222 AC: 782 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.0612 AC: 1185 AN: 19359

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.0161 AC: 871 AN: 54043

European-Finnish (FIN) AF: 0.0496 AC: 1987 AN: 40098

Middle Eastern (MID) AF: 0.0463 AC: 148 AN: 3198

European-Non Finnish (NFE) AF: 0.0656 AC: 55124 AN: 839940

Other (OTH) AF: 0.0508 AC: 2333 AN: 45924

GnomAD4 genome AF: 0.0411 AC: 4589 AN: 111637 Hom.: 119 Cov.: 22 AF XY: 0.0332 AC XY: 1124 AN XY: 33833

African (AFR) AF: 0.00811 AC: 250 AN: 30843

American (AMR) AF: 0.0262 AC: 277 AN: 10585

Ashkenazi Jewish (ASJ) AF: 0.0598 AC: 158 AN: 2643

East Asian (EAS) AF: 0.000566 AC: 2 AN: 3536

South Asian (SAS) AF: 0.0124 AC: 33 AN: 2669

European-Finnish (FIN) AF: 0.0445 AC: 269 AN: 6046

Middle Eastern (MID) AF: 0.0326 AC: 7 AN: 215

European-Non Finnish (NFE) AF: 0.0658 AC: 3481 AN: 52901

Other (OTH) AF: 0.0408 AC: 62 AN: 1518

Alfa AF: 0.0583 Hom.: 483

Bravo AF: 0.0402

ESP6500AA AF: 0.00944 AC: 36

ESP6500EA AF: 0.0704 AC: 466

ExAC AF: 0.0451 AC: 5477

EpiCase AF: 0.0618

EpiControl AF: 0.0630

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Menkes kinky-hair syndrome Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.25
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.049	D
Polyphen		0.058	B
Vest4		0.17
MPC		0.60
ClinPred		0.062	T
GERP RS		0.12
PromoterAI		0.031	Neutral
Varity_R		0.37
gMVP		0.83
Mutation Taster		=92/8	polymorphism (auto)

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

dbSNP: rs62621209; hg19: chrX-77224879; COSMIC: COSV107408272; COSMIC: COSV107408272;