Genetic Variant MIF:p.Gly52Arg (chr22-23894817-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002415.2(MIF):c.154G>C(p.Gly52Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,404,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G52C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MIF
NM_002415.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.46

Publications

0 publications found

Variant links:

Genes affected

MIF (HGNC:7097): (macrophage migration inhibitory factor) This gene encodes a lymphokine involved in cell-mediated immunity, immunoregulation, and inflammation. It plays a role in the regulation of macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids. This lymphokine and the JAB1 protein form a complex in the cytosol near the peripheral plasma membrane, which may indicate an additional role in integrin signaling pathways. [provided by RefSeq, Jul 2008]

MIF links:

ENSG00000251357 (HGNC:):

ENSG00000251357 links:

MIF-AS1 (HGNC:27669): (MIF antisense RNA 1)

MIF-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002415.2. 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
	MIF	NM_002415.2	MANE Select	c.154G>C	p.Gly52Arg	missense	Exon 2 of 3	NP_002406.1	P14174
	MIF-AS1	NR_038911.1		n.1085C>G		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MIF	ENST00000215754.8	TSL:1 MANE Select	c.154G>C	p.Gly52Arg	missense	Exon 2 of 3	ENSP00000215754.7	P14174
ENSG00000251357	ENST00000433835.3	TSL:5	c.477G>C	p.Ala159Ala	synonymous	Exon 5 of 6	ENSP00000400325.3	H7C1H1
MIF-AS1	ENST00000406213.1	TSL:1	n.1085C>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1404652

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694428

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32230

American (AMR)

AF:

0.00

AC:

AN:

38454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25312

East Asian (EAS)

AF:

0.00

AC:

AN:

36938

South Asian (SAS)

AF:

0.00

AC:

AN:

81016

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1088388

Other (OTH)

AF:

0.00

AC:

AN:

58370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.15

MutationAssessor

Pathogenic

3.8

PhyloP100

9.5

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-7.1

REVEL

Uncertain

0.64

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.95

MutPred

0.76

Gain of solvent accessibility (P = 0.0037)

MVP

0.43

MPC

2.0

ClinPred

0.99

GERP RS

3.8

PromoterAI

0.061

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.86

gMVP

0.87

Mutation Taster

=53/47

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over