chr12-48134194-G-A

Variant names:

• chr12-48134194-G-A
• rs41291963
• NM_000289.6:c.594-38G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000289.6(PFKM):​c.594-38G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00775 in 1,593,824 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (76 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (99 hom.)
• Consequence: PFKM NM_000289.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.888
• Publications: 2 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=-0.85).
• BP6: Variant 12-48134194-G-A is Benign according to our data. Variant chr12-48134194-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 255764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0194 (2950/152282) while in subpopulation AFR AF = 0.0484 (2012/41546). AF 95% confidence interval is 0.0467. There are 76 homozygotes in GnomAd4. There are 1498 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKM	NM_000289.6	c.594-38G>A		intron_variant	Intron 6 of 22	ENST00000359794.11	NP_000280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKM	ENST00000359794.11	c.594-38G>A		intron_variant	Intron 6 of 22	1	NM_000289.6	ENSP00000352842.5

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2915 AN: 152164 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0109 AC: 2739 AN: 251464 AF XY: 0.00982

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0275

Gnomad NFE exome AF: 0.00541

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00652 AC: 9400 AN: 1441542 Hom.: 99 Cov.: 29 AF XY: 0.00641 AC XY: 4603 AN XY: 718554

African (AFR) AF: 0.0479 AC: 1586 AN: 33078

American (AMR) AF: 0.00488 AC: 218 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 896 AN: 26008

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39592

South Asian (SAS) AF: 0.00471 AC: 405 AN: 85906

European-Finnish (FIN) AF: 0.0283 AC: 1512 AN: 53416

Middle Eastern (MID) AF: 0.0233 AC: 134 AN: 5748

European-Non Finnish (NFE) AF: 0.00365 AC: 3992 AN: 1093484

Other (OTH) AF: 0.0110 AC: 656 AN: 59612

GnomAD4 genome AF: 0.0194 AC: 2950 AN: 152282 Hom.: 76 Cov.: 32 AF XY: 0.0201 AC XY: 1498 AN XY: 74458

African (AFR) AF: 0.0484 AC: 2012 AN: 41546

American (AMR) AF: 0.00954 AC: 146 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 113 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.0299 AC: 317 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00450 AC: 306 AN: 68014

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.0151 Hom.: 5

Bravo AF: 0.0196

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Likely 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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.85
CADD	Benign	2.5
DANN	Benign	0.41
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41291963; hg19: chr12-48527977;