5-150848653-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001145805.2(IRGM):c.530G>A(p.Arg177Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000045 in 1,533,116 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (1 hom.)
• Consequence: IRGM NM_001145805.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.491

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035566896).
• BP6: Variant 5-150848653-G-A is Benign according to our data. Variant chr5-150848653-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2271847.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRGM	NM_001145805.2	c.530G>A	p.Arg177Gln	missense_variant	2/2	ENST00000522154.2
IRGM	NM_001346557.2	c.530G>A	p.Arg177Gln	missense_variant, splice_region_variant	2/4
IRGM	NR_170598.1	n.1645G>A		splice_region_variant, non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRGM	ENST00000522154.2	c.530G>A	p.Arg177Gln	missense_variant	2/2	1	NM_001145805.2	P1
IRGM	ENST00000520549.1	c.158G>A	p.Arg53Gln	missense_variant, splice_region_variant, NMD_transcript_variant	1/4	1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000977 AC: 14 AN: 143348 Hom.: 0 AF XY: 0.0000656 AC XY: 5 AN XY: 76220

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000831

Gnomad SAS exome AF: 0.0000480

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.000248

GnomAD4 exome AF: 0.0000463 AC: 64 AN: 1380868 Hom.: 1 Cov.: 30 AF XY: 0.0000383 AC XY: 26 AN XY: 678714

Gnomad4 AFR exome AF: 0.0000323

Gnomad4 AMR exome AF: 0.0000299

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.0000258

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000187

Gnomad4 OTH exome AF: 0.0000701

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000445 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.58
Dann	Benign	0.45
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.37	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.019
Sift	Benign	0.38	T
Sift4G	Benign	0.35	T
Polyphen		0.32	B
Vest4		0.021
MutPred		0.61		Gain of ubiquitination at K175 (P = 0.1222);
MVP		0.014
ClinPred		0.0029	T
GERP RS		-3.6
Varity_R		0.032
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs764743745; hg19: chr5-150228215;