chr12-48132936-C-T

Variant names:

• chr12-48132936-C-T
• rs11552507
• NM_000289.6:c.306C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000289.6(PFKM):​c.306C>T​(p.Ala102Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,614,122 control chromosomes in the GnomAD database, including 491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (32 hom., cov: 32)
  • Exomes 𝑓: 0.023 (459 hom.)
• Consequence: PFKM NM_000289.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.338
• Publications: 5 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 12-48132936-C-T is Benign according to our data. Variant chr12-48132936-C-T is described in ClinVar as Benign. ClinVar VariationId is 255761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0189 (2871/152270) while in subpopulation NFE AF = 0.0289 (1963/68014). AF 95% confidence interval is 0.0278. There are 32 homozygotes in GnomAd4. There are 1402 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	NM_000289.6	MANE Select	c.306C>T	p.Ala102Ala	synonymous	Exon 5 of 23	NP_000280.1	P08237-1
	PFKM	NM_001354735.1		c.615C>T	p.Ala205Ala	synonymous	Exon 8 of 26	NP_001341664.1	A0A2R8Y891
	PFKM	NM_001354736.1		c.615C>T	p.Ala205Ala	synonymous	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.306C>T	p.Ala102Ala	synonymous	Exon 5 of 23	ENSP00000352842.5	P08237-1
	PFKM	ENST00000312352.11	TSL:1	c.306C>T	p.Ala102Ala	synonymous	Exon 5 of 23	ENSP00000309438.7	P08237-1
	PFKM	ENST00000547587.5	TSL:1	c.306C>T	p.Ala102Ala	synonymous	Exon 4 of 22	ENSP00000449426.1	P08237-1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2872 AN: 152152 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.0452

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0316

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0196 AC: 4916 AN: 251300 AF XY: 0.0192

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0387

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0297

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0227 AC: 33178 AN: 1461852 Hom.: 459 Cov.: 34 AF XY: 0.0224 AC XY: 16265 AN XY: 727228

African (AFR) AF: 0.00338 AC: 113 AN: 33478

American (AMR) AF: 0.0102 AC: 455 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 963 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00466 AC: 402 AN: 86256

European-Finnish (FIN) AF: 0.0309 AC: 1651 AN: 53418

Middle Eastern (MID) AF: 0.00693 AC: 40 AN: 5768

European-Non Finnish (NFE) AF: 0.0256 AC: 28479 AN: 1111984

Other (OTH) AF: 0.0178 AC: 1072 AN: 60392

GnomAD4 genome AF: 0.0189 AC: 2871 AN: 152270 Hom.: 32 Cov.: 32 AF XY: 0.0188 AC XY: 1402 AN XY: 74448

African (AFR) AF: 0.00354 AC: 147 AN: 41562

American (AMR) AF: 0.0129 AC: 197 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 116 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4824

European-Finnish (FIN) AF: 0.0316 AC: 335 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0289 AC: 1963 AN: 68014

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.0279 Hom.: 117

Bravo AF: 0.0165

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0257

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Glycogen storage disease, type VII (5)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	10
DANN	Benign	0.67
PhyloP100		-0.34
Mutation Taster		=99/1	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: rs11552507; hg19: chr12-48526719;