chr12-48132929-G-A

Variant names:

• chr12-48132929-G-A
• rs2228500
• NM_000289.6:c.299G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000289.6(PFKM):​c.299G>A​(p.Arg100Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,613,792 control chromosomes in the GnomAD database, including 34,053 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2442 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31611 hom.)
• Consequence: PFKM NM_000289.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.594
• Publications: 44 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]

MIR6505 (HGNC:50104): (microRNA 6505) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017756522).
• BP6: Variant 12-48132929-G-A is Benign according to our data. Variant chr12-48132929-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	NM_000289.6	MANE Select	c.299G>A	p.Arg100Gln	missense	Exon 5 of 23	NP_000280.1	P08237-1
	PFKM	NM_001354735.1		c.608G>A	p.Arg203Gln	missense	Exon 8 of 26	NP_001341664.1	A0A2R8Y891
	PFKM	NM_001354736.1		c.608G>A	p.Arg203Gln	missense	Exon 8 of 26	NP_001341665.1	A0A2R8Y891

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	ENST00000359794.11	TSL:1 MANE Select	c.299G>A	p.Arg100Gln	missense	Exon 5 of 23	ENSP00000352842.5	P08237-1
	PFKM	ENST00000312352.11	TSL:1	c.299G>A	p.Arg100Gln	missense	Exon 5 of 23	ENSP00000309438.7	P08237-1
	PFKM	ENST00000547587.5	TSL:1	c.299G>A	p.Arg100Gln	missense	Exon 4 of 22	ENSP00000449426.1	P08237-1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25223 AN: 151988 Hom.: 2440 Cov.: 32

Gnomad AFR AF: 0.0724

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.178 AC: 44734 AN: 251114 AF XY: 0.182

Gnomad AFR exome AF: 0.0689

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.252

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.204 AC: 298112 AN: 1461686 Hom.: 31611 Cov.: 36 AF XY: 0.203 AC XY: 147325 AN XY: 727170

African (AFR) AF: 0.0690 AC: 2309 AN: 33478

American (AMR) AF: 0.121 AC: 5415 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 7020 AN: 26128

East Asian (EAS) AF: 0.227 AC: 8992 AN: 39698

South Asian (SAS) AF: 0.139 AC: 12001 AN: 86250

European-Finnish (FIN) AF: 0.135 AC: 7224 AN: 53418

Middle Eastern (MID) AF: 0.206 AC: 1189 AN: 5768

European-Non Finnish (NFE) AF: 0.217 AC: 241695 AN: 1111834

Other (OTH) AF: 0.203 AC: 12267 AN: 60392

GnomAD4 genome AF: 0.166 AC: 25225 AN: 152106 Hom.: 2442 Cov.: 32 AF XY: 0.163 AC XY: 12085 AN XY: 74364

African (AFR) AF: 0.0724 AC: 3006 AN: 41500

American (AMR) AF: 0.177 AC: 2711 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 979 AN: 3472

East Asian (EAS) AF: 0.242 AC: 1249 AN: 5160

South Asian (SAS) AF: 0.148 AC: 715 AN: 4818

European-Finnish (FIN) AF: 0.128 AC: 1360 AN: 10592

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14627 AN: 67960

Other (OTH) AF: 0.202 AC: 427 AN: 2110

Alfa AF: 0.200 Hom.: 10866

Bravo AF: 0.166

TwinsUK AF: 0.218 AC: 810

ALSPAC AF: 0.209 AC: 804

ESP6500AA AF: 0.0710 AC: 313

ESP6500EA AF: 0.224 AC: 1923

ExAC AF: 0.177 AC: 21515

Asia WGS AF: 0.155 AC: 538 AN: 3478

EpiCase AF: 0.229

EpiControl AF: 0.234

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Glycogen storage disease, type VII (6)
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	N
PhyloP100		0.59
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Benign	0.24	T
Sift4G	Benign	0.17	T
Polyphen		0.0030	B
Vest4		0.062
MPC		0.67
ClinPred		0.0082	T
GERP RS		1.7
Varity_R		0.13
gMVP		0.58
Mutation Taster		=98/2	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: rs2228500; hg19: chr12-48526712; COSMIC: COSV56656541; COSMIC: COSV56656541;