dbSNP rs77724219: IRGM:c.-420A>C (chr5-150847216-A-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.-420A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 152,436 control chromosomes in the GnomAD database, including 193 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 0.039 ( 193 hom., cov: 32)

Exomes 𝑓: 0.055 ( 0 hom. )

Consequence

IRGM
NM_001145805.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.356

Publications

6 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=-0.99).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRGM	NM_001145805.2 link	c.-420A>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	ENST00000522154.2	NP_001139277.1
IRGM	NM_001145805.2 link	c.-420A>C		5_prime_UTR_variant	Exon 1 of 2	ENST00000522154.2	NP_001139277.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
IRGM	ENST00000522154.2 link	c.-420A>C	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	1	NM_001145805.2	ENSP00000428220.1
IRGM	ENST00000522154.2 link	c.-420A>C	5_prime_UTR_variant	Exon 1 of 2	1	NM_001145805.2	ENSP00000428220.1
IRGM	ENST00000609660.1 link	n.414A>C	non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.0389

AC:

5921

AN:

152118

Hom.:

194

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.0305

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.0627

Gnomad FIN

AF:

0.0328

Gnomad MID

AF:

0.102

Gnomad NFE

AF:

0.0425

Gnomad OTH

AF:

0.0388

GnomAD4 exome

AF:

0.0550

AC:

AN:

200

Hom.:

Cov.:

AF XY:

0.0431

AC XY:

AN XY:

116

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.0429

AC:

AN:

140

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.0714

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0526

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.566

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

5917

AN:

152236

Hom.:

193

Cov.:

AF XY:

0.0404

AC XY:

3008

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0149

AC:

621

AN:

41548

American (AMR)

AF:

0.0305

AC:

466

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

128

AN:

3468

East Asian (EAS)

AF:

0.181

AC:

936

AN:

5180

South Asian (SAS)

AF:

0.0627

AC:

302

AN:

4814

European-Finnish (FIN)

AF:

0.0328

AC:

348

AN:

10614

Middle Eastern (MID)

AF:

0.0959

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0425

AC:

2893

AN:

68014

Other (OTH)

AF:

0.0379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

278

556

834

1112

1390

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:

0.0445

Hom.:

236

Bravo

AF:

0.0395

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

BayesDel_noAF

Benign

-0.99

CADD

Benign

2.3

(source)

DANN

Benign

0.63

PhyloP100

-0.36

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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