dbSNP rs41291967: PFKM:c.1500+32C>T (chr12-48141859-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000289.6(PFKM):c.1500+32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0077 in 1,612,842 control chromosomes in the GnomAD database, including 176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 76 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 100 hom. )

Consequence

PFKM
NM_000289.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.311

Publications

2 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: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

PFKM links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000289.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-48141859-C-T is Benign according to our data. Variant chr12-48141859-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0194 (2949/152242) while in subpopulation AFR AF = 0.0483 (2007/41540). AF 95% confidence interval is 0.0466. There are 76 homozygotes in GnomAd4. There are 1502 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 76 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000289.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PFKM	NM_000289.6	MANE Select	c.1500+32C>T	intron	N/A	NP_000280.1	P08237-1
PFKM	NM_001354735.1		c.1809+32C>T	intron	N/A	NP_001341664.1	A0A2R8Y891
PFKM	NM_001354736.1		c.1809+32C>T	intron	N/A	NP_001341665.1	A0A2R8Y891

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PFKM	ENST00000359794.11	TSL:1 MANE Select	c.1500+32C>T	intron	N/A	ENSP00000352842.5	P08237-1
PFKM	ENST00000312352.11	TSL:1	c.1500+32C>T	intron	N/A	ENSP00000309438.7	P08237-1
PFKM	ENST00000547587.5	TSL:1	c.1500+32C>T	intron	N/A	ENSP00000449426.1	P08237-1

Frequencies

GnomAD3 genomes

AF:

0.0192

AC:

2914

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0476

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00963

Gnomad ASJ

AF:

0.0325

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0300

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00451

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0109

AC:

2740

AN:

251302

AF XY:

0.00982

show subpopulations

Gnomad AFR exome

AF:

0.0498

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.0337

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0275

Gnomad NFE exome

AF:

0.00539

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.00649

AC:

9475

AN:

1460600

Hom.:

100

Cov.:

AF XY:

0.00637

AC XY:

4626

AN XY:

726710

show subpopulations

African (AFR)

AF:

0.0479

AC:

1603

AN:

33458

American (AMR)

AF:

0.00490

AC:

219

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0344

AC:

899

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00471

AC:

406

AN:

86238

European-Finnish (FIN)

AF:

0.0283

AC:

1512

AN:

53416

Middle Eastern (MID)

AF:

0.0231

AC:

133

AN:

5766

European-Non Finnish (NFE)

AF:

0.00364

AC:

4041

AN:

1110826

Other (OTH)

AF:

0.0109

AC:

660

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

571

1143

1714

2286

2857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

178

356

534

712

890

<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:

0.0194

AC:

2949

AN:

152242

Hom.:

Cov.:

AF XY:

0.0202

AC XY:

1502

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0483

AC:

2007

AN:

41540

American (AMR)

AF:

0.00961

AC:

147

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0325

AC:

113

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00249

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0300

AC:

319

AN:

10616

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00451

AC:

307

AN:

68002

Other (OTH)

AF:

0.0128

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

138

276

413

551

689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0134

Hom.:

Bravo

AF:

0.0195

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Glycogen storage disease, type VII (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.5

(source)

DANN

Benign

0.60

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over