Genetic Variant IRGM:c.-994T>C (chr5-150846642-T-C) – 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.-994T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 150,926 control chromosomes in the GnomAD database, including 5,195 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 5195 hom., cov: 32)

Exomes 𝑓: 0.031 ( 0 hom. )

Consequence

IRGM
NM_001145805.2 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.45

Publications

2 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 (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
IRGM	NM_001145805.2 link	c.-994T>C	5_prime_UTR_variant	Exon 1 of 2	ENST00000522154.2	NP_001139277.1	A1A4Y4-1
IRGM	NR_170598.1 link	n.122T>C	non_coding_transcript_exon_variant	Exon 1 of 5
IRGM	NM_001346557.2 link	c.-994T>C	5_prime_UTR_variant	Exon 1 of 4		NP_001333486.1	A1A4Y4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRGM	ENST00000522154.2 link	c.-994T>C		5_prime_UTR_variant	Exon 1 of 2	1	NM_001145805.2	ENSP00000428220.1		A1A4Y4-1
IRGM	ENST00000609660.1 link	n.-161T>C		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30381

AN:

150704

Hom.:

5181

Cov.:

show subpopulations

Gnomad AFR

AF:

0.437

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.149

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.422

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.0773

Gnomad MID

AF:

0.188

Gnomad NFE

AF:

0.0787

Gnomad OTH

AF:

0.205

GnomAD4 exome

AF:

0.0313

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0405

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.250

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0238

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.202

AC:

30436

AN:

150830

Hom.:

5195

Cov.:

AF XY:

0.202

AC XY:

14860

AN XY:

73718

show subpopulations

African (AFR)

AF:

0.437

AC:

17909

AN:

40978

American (AMR)

AF:

0.148

AC:

2246

AN:

15146

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

549

AN:

3434

East Asian (EAS)

AF:

0.423

AC:

2140

AN:

5060

South Asian (SAS)

AF:

0.198

AC:

934

AN:

4720

European-Finnish (FIN)

AF:

0.0773

AC:

813

AN:

10518

Middle Eastern (MID)

AF:

0.191

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0787

AC:

5331

AN:

67700

Other (OTH)

AF:

0.207

AC:

431

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

953

1906

2859

3812

4765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

288

576

864

1152

1440

<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:

0.0316

Hom.:

Bravo

AF:

0.224

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

3.9

(source)

DANN

Benign

0.14

PhyloP100

-1.5

PromoterAI

0.0012

Neutral

(source)

Mutation Taster

=300/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over