Genetic Variant IRGM:c.-968A>G (chr5-150846668-A-G) – 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.-968A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 151,786 control chromosomes in the GnomAD database, including 5,184 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 0.21 ( 5183 hom., cov: 32)

Exomes 𝑓: 0.047 ( 1 hom. )

Consequence

IRGM
NM_001145805.2 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.34

Publications

5 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
IRGM	NM_001145805.2	MANE Select	c.-968A>G	5_prime_UTR	Exon 1 of 2	NP_001139277.1	A1A4Y4-1
IRGM	NM_001346557.2		c.-968A>G	5_prime_UTR	Exon 1 of 4	NP_001333486.1	A1A4Y4-2
IRGM	NR_170598.1		n.148A>G	non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IRGM	ENST00000522154.2	TSL:1 MANE Select	c.-968A>G	5_prime_UTR	Exon 1 of 2	ENSP00000428220.1	A1A4Y4-1
IRGM	ENST00000951736.1		c.-829A>G	5_prime_UTR	Exon 1 of 2	ENSP00000621795.1
IRGM	ENST00000609660.1	TSL:6	n.-135A>G	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

31129

AN:

151430

Hom.:

5169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.441

Gnomad AMI

AF:

0.0341

Gnomad AMR

AF:

0.154

Gnomad ASJ

AF:

0.164

Gnomad EAS

AF:

0.432

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.0809

Gnomad MID

AF:

0.201

Gnomad NFE

AF:

0.0812

Gnomad OTH

AF:

0.209

GnomAD4 exome

AF:

0.0466

AC:

AN:

236

Hom.:

Cov.:

AF XY:

0.0484

AC XY:

AN XY:

186

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

AN:

East Asian (EAS)

AF:

0.200

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0300

AC:

AN:

200

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.206

AC:

31182

AN:

151550

Hom.:

5183

Cov.:

AF XY:

0.206

AC XY:

15255

AN XY:

74062

show subpopulations

African (AFR)

AF:

0.441

AC:

18175

AN:

41216

American (AMR)

AF:

0.153

AC:

2333

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.164

AC:

568

AN:

3464

East Asian (EAS)

AF:

0.433

AC:

2222

AN:

5130

South Asian (SAS)

AF:

0.206

AC:

982

AN:

4760

European-Finnish (FIN)

AF:

0.0809

AC:

854

AN:

10554

Middle Eastern (MID)

AF:

0.205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0812

AC:

5516

AN:

67896

Other (OTH)

AF:

0.211

AC:

441

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

949

1897

2846

3794

4743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

300

600

900

1200

1500

<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:

0.148

Hom.:

308

Asia WGS

AF:

0.321

AC:

1118

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

3.4

(source)

DANN

Benign

0.13

PhyloP100

-1.3

PromoterAI

0.016

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over