chr12-48124481-A-C

Variant names:

• chr12-48124481-A-C
• rs10875746
• NM_000289.6:c.85+1622A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000289.6(PFKM):​c.85+1622A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 152,144 control chromosomes in the GnomAD database, including 3,536 homozygotes. 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: 𝑓 0.21 (3536 hom., cov: 32)
• Consequence: PFKM NM_000289.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.259
• Publications: 17 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6	c.85+1622A>C		intron_variant	Intron 2 of 22	ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.85+1622A>C		intron_variant	Intron 2 of 22	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32155 AN: 152026 Hom.: 3533 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.241

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.211 AC: 32178 AN: 152144 Hom.: 3536 Cov.: 32 AF XY: 0.207 AC XY: 15373 AN XY: 74400

African (AFR) AF: 0.195 AC: 8094 AN: 41500

American (AMR) AF: 0.205 AC: 3137 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1109 AN: 3468

East Asian (EAS) AF: 0.242 AC: 1253 AN: 5170

South Asian (SAS) AF: 0.146 AC: 706 AN: 4820

European-Finnish (FIN) AF: 0.132 AC: 1401 AN: 10600

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15764 AN: 67976

Other (OTH) AF: 0.239 AC: 505 AN: 2112

Alfa AF: 0.219 Hom.: 2762

Bravo AF: 0.218

Asia WGS AF: 0.161 AC: 560 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.58
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10875746; hg19: chr12-48518264;