chr12-48145699-T-G

Variant names:

• chr12-48145699-T-G
• rs8716
• NM_000289.6:c.2334T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001354735.1(PFKM):​c.2643T>G​(p.Ala881Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,613,540 control chromosomes in the GnomAD database, including 106,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A881A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.29 (7298 hom., cov: 32)
  • Exomes 𝑓: 0.36 (99245 hom.)
• Consequence: PFKM NM_001354735.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.338
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-48145699-T-G is Benign according to our data. Variant chr12-48145699-T-G is described in ClinVar as Benign. ClinVar VariationId is 255758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.338 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	NM_000289.6	MANE Select	c.2334T>G	p.Ala778Ala	synonymous	Exon 23 of 23	NP_000280.1
	PFKM	NM_001354735.1		c.2643T>G	p.Ala881Ala	synonymous	Exon 26 of 26	NP_001341664.1
	PFKM	NM_001354736.1		c.2643T>G	p.Ala881Ala	synonymous	Exon 26 of 26	NP_001341665.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	ENST00000359794.11	TSL:1 MANE Select	c.2334T>G	p.Ala778Ala	synonymous	Exon 23 of 23	ENSP00000352842.5
	PFKM	ENST00000312352.11	TSL:1	c.2334T>G	p.Ala778Ala	synonymous	Exon 23 of 23	ENSP00000309438.7
	PFKM	ENST00000547587.5	TSL:1	c.2334T>G	p.Ala778Ala	synonymous	Exon 22 of 22	ENSP00000449426.1

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43408 AN: 151998 Hom.: 7299 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.296

GnomAD2 exomes AF: 0.316 AC: 79487 AN: 251320 AF XY: 0.328

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.347

Gnomad EAS exome AF: 0.0114

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.360 AC: 526152 AN: 1461424 Hom.: 99245 Cov.: 38 AF XY: 0.361 AC XY: 262772 AN XY: 727052

African (AFR) AF: 0.115 AC: 3853 AN: 33478

American (AMR) AF: 0.244 AC: 10911 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 9189 AN: 26134

East Asian (EAS) AF: 0.00645 AC: 256 AN: 39700

South Asian (SAS) AF: 0.373 AC: 32209 AN: 86246

European-Finnish (FIN) AF: 0.354 AC: 18921 AN: 53414

Middle Eastern (MID) AF: 0.351 AC: 2020 AN: 5762

European-Non Finnish (NFE) AF: 0.386 AC: 428770 AN: 1111598

Other (OTH) AF: 0.332 AC: 20023 AN: 60370

GnomAD4 genome AF: 0.285 AC: 43409 AN: 152116 Hom.: 7298 Cov.: 32 AF XY: 0.284 AC XY: 21092 AN XY: 74334

African (AFR) AF: 0.123 AC: 5130 AN: 41546

American (AMR) AF: 0.269 AC: 4105 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1239 AN: 3468

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5188

South Asian (SAS) AF: 0.349 AC: 1677 AN: 4810

European-Finnish (FIN) AF: 0.370 AC: 3908 AN: 10556

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26181 AN: 67958

Other (OTH) AF: 0.295 AC: 624 AN: 2116

Alfa AF: 0.355 Hom.: 14934

Bravo AF: 0.268

Asia WGS AF: 0.208 AC: 726 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.379

ClinVar

ClinVar submissions as Germline

Significance: 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 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.73
DANN	Benign	0.49
PhyloP100		-0.34
Mutation Taster		=50/50

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: rs8716; hg19: chr12-48539482; COSMIC: COSV56660739; COSMIC: COSV56660739;