Genetic Variant IRGM:c.-1124A>G (chr5-150846512-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.-1124A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 149,886 control chromosomes in the GnomAD database, including 5,553 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 ( 5553 hom., cov: 32)

Exomes 𝑓: 0.031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IRGM
NM_001145805.2 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.34

Publications

4 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=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
IRGM	NM_001145805.2 link	c.-1124A>G	upstream_gene_variant	ENST00000522154.2	NP_001139277.1	A1A4Y4-1
IRGM	NM_001346557.2 link	c.-1124A>G	upstream_gene_variant		NP_001333486.1	A1A4Y4-2
IRGM	NR_170598.1 link	n.-9A>G	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRGM	ENST00000522154.2 link	c.-1124A>G		upstream_gene_variant		1	NM_001145805.2	ENSP00000428220.1		A1A4Y4-1

Frequencies

GnomAD3 genomes

AF:

0.206

AC:

30848

AN:

149768

Hom.:

5532

Cov.:

show subpopulations

Gnomad AFR

AF:

0.458

Gnomad AMI

AF:

0.0341

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.426

Gnomad SAS

AF:

0.204

Gnomad FIN

AF:

0.0750

Gnomad MID

AF:

0.198

Gnomad NFE

AF:

0.0765

Gnomad OTH

AF:

0.205

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0313

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0417

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.206

AC:

30912

AN:

149886

Hom.:

5553

Cov.:

AF XY:

0.206

AC XY:

15087

AN XY:

73312

show subpopulations

African (AFR)

AF:

0.458

AC:

18595

AN:

40586

American (AMR)

AF:

0.147

AC:

2217

AN:

15066

Ashkenazi Jewish (ASJ)

AF:

0.158

AC:

537

AN:

3408

East Asian (EAS)

AF:

0.426

AC:

2140

AN:

5018

South Asian (SAS)

AF:

0.204

AC:

968

AN:

4754

European-Finnish (FIN)

AF:

0.0750

AC:

786

AN:

10486

Middle Eastern (MID)

AF:

0.203

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0766

AC:

5152

AN:

67298

Other (OTH)

AF:

0.206

AC:

428

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

960

1920

2879

3839

4799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.135

Hom.:

334

Bravo

AF:

0.231

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

2.1

(source)

DANN

Benign

0.31

PhyloP100

-1.3

PromoterAI

0.020

Neutral

(source)

Splicing

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