X-77969382-C-T

Position:

chrX-77969382-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★).

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein
PGAM4	NM_001029891.3 linkuse as main transcript	c.257G>A	p.Arg86His	missense_variant	1/1	ENST00000458128.3	NP_001025062.1
ATP7A	NM_000052.7 linkuse as main transcript	c.-21-2239C>T		intron_variant		ENST00000341514.11	NP_000043.4
ATP7A	NM_001282224.2 linkuse as main transcript	c.-21-2239C>T		intron_variant			NP_001269153.1
ATP7A	NR_104109.2 linkuse as main transcript	n.144-2239C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGAM4	ENST00000458128.3 linkuse as main transcript	c.257G>A	p.Arg86His	missense_variant	1/1		NM_001029891.3	ENSP00000412189	P1
ATP7A	ENST00000341514.11 linkuse as main transcript	c.-21-2239C>T		intron_variant		1	NM_000052.7	ENSP00000345728	P1	Q04656-1

Frequencies

GnomAD3 genomes

AF:

0.0411

AC:

4590

AN:

111584

Hom.:

119

Cov.:

AF XY:

0.0333

AC XY:

1125

AN XY:

33770

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0525

AC XY:

18926

AN XY:

360550

show subpopulations

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.:

AF XY:

0.0332

AC XY:

1124

AN XY:

33833

show subpopulations

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:

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

LINK: link

Submissions by phenotype

Menkes kinky-hair syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.030

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.8e-23

P;P;P;P

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.25

Sift

Uncertain

0.017

Sift4G

Uncertain

0.049

Polyphen

0.058

Vest4

0.17

MPC

0.60

ClinPred

0.062

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over