12-48108360-G-A

Variant names:

• chr12-48108360-G-A
• rs73102080
• NM_001354735.1:c.205+166G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001354735.1(PFKM):​c.205+166G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 152,064 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.023 (61 hom., cov: 32)
• Consequence: PFKM NM_001354735.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.473
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-48108360-G-A is Benign according to our data. Variant chr12-48108360-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1201899.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0232 (3531/152064) while in subpopulation NFE AF = 0.0349 (2374/67996). AF 95% confidence interval is 0.0337. There are 61 homozygotes in GnomAd4. There are 1703 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_001354735.1	c.205+166G>A		intron_variant	Intron 3 of 25		NP_001341664.1
PFKM	NM_001354736.1	c.205+166G>A		intron_variant	Intron 3 of 25		NP_001341665.1
PFKM	NM_001166686.2	c.205+166G>A		intron_variant	Intron 3 of 24		NP_001160158.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000642730.1	c.205+166G>A		intron_variant	Intron 3 of 25			ENSP00000496597.1
PFKM	ENST00000550257.7	c.214+166G>A		intron_variant	Intron 2 of 23	4		ENSP00000447997.3
PFKM	ENST00000340802.12	c.205+166G>A		intron_variant	Intron 3 of 24	2		ENSP00000345771.6

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3530 AN: 151946 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00613

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0225

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

GnomAD4 genome AF: 0.0232 AC: 3531 AN: 152064 Hom.: 61 Cov.: 32 AF XY: 0.0229 AC XY: 1703 AN XY: 74354

African (AFR) AF: 0.00613 AC: 254 AN: 41412

American (AMR) AF: 0.0165 AC: 252 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4822

European-Finnish (FIN) AF: 0.0412 AC: 436 AN: 10586

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0349 AC: 2374 AN: 67996

Other (OTH) AF: 0.0223 AC: 47 AN: 2112

Alfa AF: 0.0282 Hom.: 10

Bravo AF: 0.0222

Asia WGS AF: 0.00462 AC: 17 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 07, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.8
DANN	Benign	0.53
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73102080; hg19: chr12-48502143;