Genetic Variant PFKM:c.1127+45G>T (chr12-48139394-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001354735.1(PFKM):c.1436+45G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000749 in 1,334,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

PFKM
NM_001354735.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.35

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354735.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PFKM	NM_000289.6	MANE Select	c.1127+45G>T	intron	N/A	NP_000280.1
PFKM	NM_001354735.1		c.1436+45G>T	intron	N/A	NP_001341664.1
PFKM	NM_001354736.1		c.1436+45G>T	intron	N/A	NP_001341665.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PFKM	ENST00000359794.11	TSL:1 MANE Select	c.1127+45G>T	intron	N/A	ENSP00000352842.5
PFKM	ENST00000312352.11	TSL:1	c.1127+45G>T	intron	N/A	ENSP00000309438.7
PFKM	ENST00000547587.5	TSL:1	c.1127+45G>T	intron	N/A	ENSP00000449426.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.49e-7

AC:

AN:

1334236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

670514

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30978

American (AMR)

AF:

0.00

AC:

AN:

44464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25284

East Asian (EAS)

AF:

0.00

AC:

AN:

39052

South Asian (SAS)

AF:

0.00

AC:

AN:

83496

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5472

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

996926

Other (OTH)

AF:

0.00

AC:

AN:

56168

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.23

(source)

DANN

Benign

0.49

PhyloP100

-1.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over