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

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

Publications

34 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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

GnomAD2 exomes

AF:

0.0487

AC:

7518

AN:

154238

AF XY:

0.0503

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 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

African (AFR)

AF:

0.0168

AC:

530

AN:

31598

American (AMR)

AF:

0.0206

AC:

734

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.0399

AC:

1006

AN:

25182

East Asian (EAS)

AF:

0.158

AC:

5683

AN:

35876

South Asian (SAS)

AF:

0.0618

AC:

4894

AN:

79236

European-Finnish (FIN)

AF:

0.0293

AC:

1446

AN:

49276

Middle Eastern (MID)

AF:

0.0697

AC:

397

AN:

5698

European-Non Finnish (NFE)

AF:

0.0419

AC:

45238

AN:

1078944

Other (OTH)

AF:

0.0464

AC:

2693

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

3588

7176

10764

14352

17940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1750

3500

5250

7000

8750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0389

AC:

5918

AN:

152316

Hom.:

192

Cov.:

AF XY:

0.0404

AC XY:

3007

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0150

AC:

623

AN:

41578

American (AMR)

AF:

0.0306

AC:

468

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0372

AC:

129

AN:

3472

East Asian (EAS)

AF:

0.180

AC:

931

AN:

5176

South Asian (SAS)

AF:

0.0626

AC:

302

AN:

4826

European-Finnish (FIN)

AF:

0.0327

AC:

347

AN:

10616

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0426

AC:

2895

AN:

68026

Other (OTH)

AF:

0.0379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

285

571

856

1142

1427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0435

Hom.:

677

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

(source)

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

PhyloP100

2.1

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over