Genetic Variant NM_001029891.3:c.123C>T (chrX-77969516-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001029891.3(PGAM4):c.123C>T(p.Gly41Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,209,181 control chromosomes in the GnomAD database, including 2 homozygotes. There are 69 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.00017 ( 2 hom. 59 hem. )

Consequence

PGAM4
NM_001029891.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.738

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

glycogen storage disease due to phosphoglycerate kinase 1 deficiency
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

PGK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant X-77969516-G-A is Benign according to our data. Variant chrX-77969516-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2660963.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.738 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 10 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001029891.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PGAM4	NM_001029891.3	MANE Select	c.123C>T	p.Gly41Gly	synonymous	Exon 1 of 1	NP_001025062.1	Q8N0Y7
ATP7A	NM_000052.7	MANE Select	c.-21-2105G>A		intron	N/A	NP_000043.4	Q04656-1
ATP7A	NM_001282224.2		c.-21-2105G>A		intron	N/A	NP_001269153.1	Q04656-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PGAM4	ENST00000458128.3	TSL:6 MANE Select	c.123C>T	p.Gly41Gly	synonymous	Exon 1 of 1	ENSP00000412189.1	Q8N0Y7
ATP7A	ENST00000341514.11	TSL:1 MANE Select	c.-21-2105G>A		intron	N/A	ENSP00000345728.6	Q04656-1
ATP7A	ENST00000689767.1		c.-21-2105G>A		intron	N/A	ENSP00000509406.1	A0A8I5KWA8

Frequencies

GnomAD3 genomes

AF:

0.000215

AC:

AN:

111876

Hom.:

Cov.:

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:

0.00681

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000591

AC:

108

AN:

182671

AF XY:

0.000474

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00772

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000175

AC:

192

AN:

1097255

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

363193

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26371

American (AMR)

AF:

0.00

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00593

AC:

179

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54107

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40517

Middle Eastern (MID)

AF:

0.000292

AC:

AN:

3427

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

842038

Other (OTH)

AF:

0.000174

AC:

AN:

46004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000205

AC:

AN:

111926

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

AN XY:

34122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30913

American (AMR)

AF:

0.00

AC:

AN:

10595

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00655

AC:

AN:

3514

South Asian (SAS)

AF:

0.00

AC:

AN:

2683

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6065

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53104

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000423

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.0

(source)

DANN

Benign

0.97

PhyloP100

-0.74

PromoterAI

0.054

Neutral

(source)

Mutation Taster

=84/16

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over