Genetic Variant NM_001354735.1:c.12C>T (chr12-48107385-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_001354735.1(PFKM):c.12C>T(p.Asp4Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,596,808 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

PFKM
NM_001354735.1 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0130

Publications

0 publications found

Variant links:

Genes affected

PFKM (HGNC:8877): (phosphofructokinase, muscle) Three phosphofructokinase isozymes exist in humans: muscle, liver and platelet. These isozymes function as subunits of the mammalian tetramer phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. Tetramer composition varies depending on tissue type. This gene encodes the muscle-type isozyme. Mutations in this gene have been associated with glycogen storage disease type VII, also known as Tarui disease. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]

PFKM Gene-Disease associations (from GenCC):

glycogen storage disease VII
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, Ambry Genetics

PFKM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 12-48107385-C-T is Benign according to our data. Variant chr12-48107385-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2428748.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.013 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
PFKM	NM_001354735.1 link	c.12C>T	p.Asp4Asp	synonymous_variant	Exon 2 of 26	NP_001341664.1
PFKM	NM_001354736.1 link	c.12C>T	p.Asp4Asp	synonymous_variant	Exon 2 of 26	NP_001341665.1
PFKM	NM_001166686.2 link	c.12C>T	p.Asp4Asp	synonymous_variant	Exon 2 of 25	NP_001160158.1	P08237-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
PFKM	ENST00000642730.1 link	c.12C>T	p.Asp4Asp	synonymous_variant	Exon 2 of 26		ENSP00000496597.1	A0A2R8Y891
PFKM	ENST00000340802.12 link	c.12C>T	p.Asp4Asp	synonymous_variant	Exon 2 of 25	2	ENSP00000345771.6	P08237-3
PFKM	ENST00000549366.5 link	c.12C>T	p.Asp4Asp	synonymous_variant	Exon 2 of 7	4	ENSP00000449622.1	F8VVE3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000256

AC:

AN:

234250

AF XY:

0.00000780

show subpopulations

Gnomad AFR exome

AF:

0.0000662

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000459

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000727

AC:

105

AN:

1444698

Hom.:

Cov.:

AF XY:

0.0000751

AC XY:

AN XY:

719340

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000919

AC:

102

AN:

1109484

Other (OTH)

AF:

0.00

AC:

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000151

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Glycogen storage disease, type VII

Benign:1

Nov 23, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

-0.013

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_001354735.1:c.12C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over