rs2269935

Variant names:

• chr12-48122681-G-T
• rs2269935
• ENST00000547587.5:c.-94G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-48122681-G-T
• chr12-48122681-G-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001166687.2(PFKM):​c.-9+4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 1,591,546 control chromosomes in the GnomAD database, including 33,215 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2407 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30808 hom.)
• Consequence: PFKM NM_001166687.2 splice_region, intron
• Scores: Splicing: ADA: 0.004091
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.79
• 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-48122681-G-T is Benign according to our data. Variant chr12-48122681-G-T is described in ClinVar as Benign. ClinVar VariationId is 676173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166687.2. 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.-8-86G>T		intron	N/A	NP_000280.1	P08237-1
	PFKM	NM_001166688.2		c.-94G>T		5_prime_UTR	Exon 1 of 22	NP_001160160.1	P08237-1
	PFKM	NM_001354735.1		c.302-86G>T		intron	N/A	NP_001341664.1	A0A2R8Y891

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKM	ENST00000547587.5	TSL:1	c.-94G>T		5_prime_UTR	Exon 1 of 22	ENSP00000449426.1	P08237-1
	PFKM	ENST00000359794.11	TSL:1 MANE Select	c.-8-86G>T		intron	N/A	ENSP00000352842.5	P08237-1
	PFKM	ENST00000312352.11	TSL:1	c.-9+4G>T		splice_region intron	N/A	ENSP00000309438.7	P08237-1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24995 AN: 152124 Hom.: 2407 Cov.: 32

Gnomad AFR AF: 0.0706

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.202

GnomAD4 exome AF: 0.203 AC: 291801 AN: 1439304 Hom.: 30808 Cov.: 32 AF XY: 0.201 AC XY: 143534 AN XY: 714316

African (AFR) AF: 0.0653 AC: 2175 AN: 33302

American (AMR) AF: 0.122 AC: 5003 AN: 41028

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 6935 AN: 25594

East Asian (EAS) AF: 0.221 AC: 8693 AN: 39292

South Asian (SAS) AF: 0.124 AC: 10403 AN: 83654

European-Finnish (FIN) AF: 0.134 AC: 6664 AN: 49826

Middle Eastern (MID) AF: 0.202 AC: 1078 AN: 5344

European-Non Finnish (NFE) AF: 0.217 AC: 238863 AN: 1101666

Other (OTH) AF: 0.201 AC: 11987 AN: 59598

GnomAD4 genome AF: 0.164 AC: 24990 AN: 152242 Hom.: 2407 Cov.: 32 AF XY: 0.160 AC XY: 11945 AN XY: 74454

African (AFR) AF: 0.0705 AC: 2929 AN: 41544

American (AMR) AF: 0.175 AC: 2681 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 991 AN: 3472

East Asian (EAS) AF: 0.237 AC: 1226 AN: 5168

South Asian (SAS) AF: 0.132 AC: 639 AN: 4826

European-Finnish (FIN) AF: 0.127 AC: 1349 AN: 10620

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

European-Non Finnish (NFE) AF: 0.215 AC: 14599 AN: 67998

Other (OTH) AF: 0.201 AC: 424 AN: 2110

Alfa AF: 0.154 Hom.: 683

Bravo AF: 0.164

Asia WGS AF: 0.150 AC: 519 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glycogen storage disease, type VII (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.94
PhyloP100		1.8
PromoterAI		-0.071	Neutral
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0041
dbscSNV1_RF	Benign	0.036
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: rs2269935; hg19: chr12-48516464; COSMIC: COSV56656445; COSMIC: COSV56656445;