dbSNP rs72553867: IRGM:p.Thr94Lys (chr5-150848404-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001145805.2(IRGM):c.281C>A(p.Thr94Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,551,828 control chromosomes in the GnomAD database, including 2,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.039 ( 192 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1836 hom. )

Consequence

IRGM
NM_001145805.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.06

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002975881).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRGM	NM_001145805.2 link	c.281C>A	p.Thr94Lys	missense_variant	Exon 2 of 2	ENST00000522154.2	NP_001139277.1	A1A4Y4-1
IRGM	NM_001346557.2 link	c.281C>A	p.Thr94Lys	missense_variant	Exon 2 of 4		NP_001333486.1	A1A4Y4-2
IRGM	NR_170598.1 link	n.1396C>A		non_coding_transcript_exon_variant	Exon 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRGM	ENST00000522154.2 link	c.281C>A	p.Thr94Lys	missense_variant	Exon 2 of 2	1	NM_001145805.2	ENSP00000428220.1		A1A4Y4-1
IRGM	ENST00000520549.1 link	n.-95C>A		upstream_gene_variant		1		ENSP00000429819.1		A0A9H4B933

Frequencies

GnomAD3 genomes

AF:

0.0389

AC:

5924

AN:

152200

Hom.:

194

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.0306

Gnomad ASJ

AF:

0.0372

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.0625

Gnomad FIN

AF:

0.0327

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0426

Gnomad OTH

AF:

0.0388

GnomAD3 exomes

AF:

0.0487

AC:

7518

AN:

154238

Hom.:

346

AF XY:

0.0503

AC XY:

4120

AN XY:

81832

show subpopulations

Gnomad AFR exome

AF:

0.0134

Gnomad AMR exome

AF:

0.0191

Gnomad ASJ exome

AF:

0.0383

Gnomad EAS exome

AF:

0.182

Gnomad SAS exome

AF:

0.0624

Gnomad FIN exome

AF:

0.0325

Gnomad NFE exome

AF:

0.0417

Gnomad OTH exome

AF:

0.0432

GnomAD4 exome

AF:

0.0447

AC:

62621

AN:

1399512

Hom.:

1836

Cov.:

AF XY:

0.0453

AC XY:

31300

AN XY:

690276

show subpopulations

Gnomad4 AFR exome

AF:

0.0168

Gnomad4 AMR exome

AF:

0.0206

Gnomad4 ASJ exome

AF:

0.0399

Gnomad4 EAS exome

AF:

0.158

Gnomad4 SAS exome

AF:

0.0618

Gnomad4 FIN exome

AF:

0.0293

Gnomad4 NFE exome

AF:

0.0419

Gnomad4 OTH exome

AF:

0.0464

GnomAD4 genome

AF:

0.0389

AC:

5918

AN:

152316

Hom.:

192

Cov.:

AF XY:

0.0404

AC XY:

3007

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0150

Gnomad4 AMR

AF:

0.0306

Gnomad4 ASJ

AF:

0.0372

Gnomad4 EAS

AF:

0.180

Gnomad4 SAS

AF:

0.0626

Gnomad4 FIN

AF:

0.0327

Gnomad4 NFE

AF:

0.0426

Gnomad4 OTH

AF:

0.0379

Alfa

AF:

0.0438

Hom.:

331

Bravo

AF:

0.0395

TwinsUK

AF:

0.0369

AC:

137

ALSPAC

AF:

0.0467

AC:

180

ESP6500AA

AF:

0.0137

AC:

ESP6500EA

AF:

0.0402

AC:

128

ExAC

AF:

0.0437

AC:

1018

Asia WGS

AF:

0.0920

AC:

320

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.27

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.11

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.052

Polyphen

0.99

Vest4

0.056

ClinPred

0.071

GERP RS

-4.0

Varity_R

0.66

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over