Genetic Variant IRGM:p.Val87Met (chr5-150848382-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001145805.2(IRGM):c.259G>A(p.Val87Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. V87L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

IRGM
NM_001145805.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.46

Publications

0 publications found

Variant links:

Genes affected

IRGM (HGNC:29597): (immunity related GTPase M) This gene encodes a member of the p47 immunity-related GTPase family. The encoded protein may play a role in the innate immune response by regulating autophagy formation in response to intracellular pathogens. Polymorphisms that affect the normal expression of this gene are associated with a susceptibility to Crohn's disease and tuberculosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2016]

IRGM links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21978226).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145805.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRGM	NM_001145805.2	MANE Select	c.259G>A	p.Val87Met	missense	Exon 2 of 2	NP_001139277.1	A1A4Y4-1
IRGM	NM_001346557.2		c.259G>A	p.Val87Met	missense	Exon 2 of 4	NP_001333486.1	A1A4Y4-2
IRGM	NR_170598.1		n.1374G>A		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRGM	ENST00000522154.2	TSL:1 MANE Select	c.259G>A	p.Val87Met	missense	Exon 2 of 2	ENSP00000428220.1	A1A4Y4-1
IRGM	ENST00000951736.1		c.259G>A	p.Val87Met	missense	Exon 2 of 2	ENSP00000621795.1
IRGM	ENST00000520549.1	TSL:1	n.-117G>A		upstream_gene	N/A	ENSP00000429819.1	A0A9H4B933

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399536

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35876

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078966

Other (OTH)

AF:

0.00

AC:

AN:

58000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.064

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.70

M_CAP

Benign

0.010

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

PhyloP100

1.5

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.0

REVEL

Benign

0.077

Sift

Benign

0.055

Sift4G

Benign

0.093

Polyphen

0.99

Vest4

0.10

MutPred

0.54

Loss of stability (P = 0.1407)

MVP

0.048

ClinPred

0.20

GERP RS

-2.1

Varity_R

0.12

gMVP

0.11

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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