X-77969382-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 5.51

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 Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
PGAM4	NM_001029891.3	c.257G>A	p.Arg86His	missense_variant	1/1	ENST00000458128.3
ATP7A	NM_000052.7	c.-21-2239C>T		intron_variant		ENST00000341514.11
ATP7A	NM_001282224.2	c.-21-2239C>T		intron_variant
ATP7A	NR_104109.2	n.144-2239C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAM4	ENST00000458128.3	c.257G>A	p.Arg86His	missense_variant	1/1		NM_001029891.3	P1
ATP7A	ENST00000341514.11	c.-21-2239C>T		intron_variant		1	NM_000052.7	P1

Frequencies

GnomAD3 genomes AF: 0.0411 AC: 4590 AN: 111584 Hom.: 119 Cov.: 22 AF XY: 0.0333 AC XY: 1125 AN XY: 33770

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

GnomAD3 exomes AF: 0.0441 AC: 7986 AN: 181003 Hom.: 170 AF XY: 0.0431 AC XY: 2873 AN XY: 66653

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 SAS exome AF: 0.0167

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

Gnomad4 AFR exome AF: 0.00744

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.0612

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.0496

Gnomad4 NFE exome AF: 0.0656

Gnomad4 OTH exome AF: 0.0508

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

Gnomad4 AFR AF: 0.00811

Gnomad4 AMR AF: 0.0262

Gnomad4 ASJ AF: 0.0598

Gnomad4 EAS AF: 0.000566

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.0445

Gnomad4 NFE AF: 0.0658

Gnomad4 OTH AF: 0.0408

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Menkes kinky-hair syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

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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
MutationTaster	Benign	1.8e-23	P;P;P;P
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
Varity_R		0.37
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs62621209; hg19: chrX-77224879;