NM_001354735.1:c.205+123A>G

Variant names:

• chr12-48108317-A-G
• rs725454
• NM_001354735.1:c.205+123A>G

Variant summary

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

The NM_001354735.1(PFKM):​c.205+123A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 780,738 control chromosomes in the GnomAD database, including 16,172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2671 hom., cov: 31)
  • Exomes 𝑓: 0.20 (13501 hom.)
• Consequence: PFKM NM_001354735.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.24
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-48108317-A-G is Benign according to our data. Variant chr12-48108317-A-G is described in ClinVar as [Benign]. Clinvar id is 676170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_001354735.1	c.205+123A>G		intron_variant	Intron 3 of 25		NP_001341664.1
PFKM	NM_001354736.1	c.205+123A>G		intron_variant	Intron 3 of 25		NP_001341665.1
PFKM	NM_001166686.2	c.205+123A>G		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+123A>G		intron_variant	Intron 3 of 25			ENSP00000496597.1
PFKM	ENST00000550257.7	c.214+123A>G		intron_variant	Intron 2 of 23	4		ENSP00000447997.3
PFKM	ENST00000340802.12	c.205+123A>G		intron_variant	Intron 3 of 24	2		ENSP00000345771.6

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27475 AN: 151888 Hom.: 2669 Cov.: 31

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.200 AC: 125501 AN: 628732 Hom.: 13501 AF XY: 0.198 AC XY: 63912 AN XY: 323406

African (AFR) AF: 0.126 AC: 1975 AN: 15644

American (AMR) AF: 0.130 AC: 2948 AN: 22624

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 3702 AN: 13688

East Asian (EAS) AF: 0.217 AC: 6840 AN: 31484

South Asian (SAS) AF: 0.128 AC: 4561 AN: 35528

European-Finnish (FIN) AF: 0.134 AC: 4103 AN: 30524

Middle Eastern (MID) AF: 0.204 AC: 761 AN: 3724

European-Non Finnish (NFE) AF: 0.212 AC: 94487 AN: 444832

Other (OTH) AF: 0.200 AC: 6124 AN: 30684

GnomAD4 genome AF: 0.181 AC: 27477 AN: 152006 Hom.: 2671 Cov.: 31 AF XY: 0.177 AC XY: 13135 AN XY: 74312

African (AFR) AF: 0.125 AC: 5170 AN: 41458

American (AMR) AF: 0.183 AC: 2798 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 986 AN: 3464

East Asian (EAS) AF: 0.236 AC: 1218 AN: 5158

South Asian (SAS) AF: 0.147 AC: 706 AN: 4800

European-Finnish (FIN) AF: 0.128 AC: 1356 AN: 10574

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14642 AN: 67970

Other (OTH) AF: 0.212 AC: 448 AN: 2112

Alfa AF: 0.208 Hom.: 5293

Bravo AF: 0.183

Asia WGS AF: 0.154 AC: 535 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.9
DANN	Benign	0.64
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs725454; hg19: chr12-48502100; COSMIC: COSV50307328; COSMIC: COSV50307328;