Variant rs376654190 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001029891.3(PGAM4):c.649G>T(p.Val217Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,209,631 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 3 hem. )

Consequence

PGAM4
NM_001029891.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.73

Variant links:

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]

PGAM4 links:

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]

ATP7A links:

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 links:

ATP7A (HGNC:):

ATP7A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.809

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGAM4	NM_001029891.3 linkuse as main transcript	c.649G>T	p.Val217Phe	missense_variant	1/1	ENST00000458128.3	NP_001025062.1	Q8N0Y7
ATP7A	NM_000052.7 linkuse as main transcript	c.-21-2631C>A		intron_variant		ENST00000341514.11	NP_000043.4	Q04656-1B4DRW0Q762B6
ATP7A	NM_001282224.2 linkuse as main transcript	c.-21-2631C>A		intron_variant			NP_001269153.1	Q04656-5B4DRW0Q762B6
ATP7A	NR_104109.2 linkuse as main transcript	n.144-2631C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGAM4	ENST00000458128.3 linkuse as main transcript	c.649G>T	p.Val217Phe	missense_variant	1/1	6	NM_001029891.3	ENSP00000412189.1		Q8N0Y7
ATP7A	ENST00000341514.11 linkuse as main transcript	c.-21-2631C>A		intron_variant		1	NM_000052.7	ENSP00000345728.6		Q04656-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112249

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34401

show subpopulations

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:

0.0000563

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183319

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67811

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000489

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1097382

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000831

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112249

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34401

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000563

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.76

M_CAP

Benign

0.012

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

3.5

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.010

Polyphen

0.99

Vest4

0.63

MVP

0.67

MPC

1.4

ClinPred

0.84

GERP RS

0.12

Varity_R

0.48

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over