5-150848436-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001145805.2(IRGM):c.313C>T(p.Leu105=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,551,610 control chromosomes in the GnomAD database, including 18,592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (5257 hom., cov: 32)
  • Exomes 𝑓: 0.11 (13335 hom.)
• Consequence: IRGM NM_001145805.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: 0.655

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP7: Synonymous conserved (PhyloP=0.655 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRGM	NM_001145805.2	c.313C>T	p.Leu105=	synonymous_variant	2/2	ENST00000522154.2
IRGM	NM_001346557.2	c.313C>T	p.Leu105=	synonymous_variant	2/4
IRGM	NR_170598.1	n.1428C>T		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRGM	ENST00000522154.2	c.313C>T	p.Leu105=	synonymous_variant	2/2	1	NM_001145805.2	P1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31482 AN: 152052 Hom.: 5243 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.0821

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.0819

Gnomad OTH AF: 0.211

GnomAD3 exomes AF: 0.165 AC: 25447 AN: 154216 Hom.: 3159 AF XY: 0.164 AC XY: 13452 AN XY: 81810

Gnomad AFR exome AF: 0.455

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.440

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.0816

Gnomad NFE exome AF: 0.0900

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.109 AC: 153155 AN: 1399440 Hom.: 13335 Cov.: 33 AF XY: 0.111 AC XY: 76783 AN XY: 690246

Gnomad4 AFR exome AF: 0.454

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.0839

Gnomad4 NFE exome AF: 0.0790

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.207 AC: 31535 AN: 152170 Hom.: 5257 Cov.: 32 AF XY: 0.207 AC XY: 15406 AN XY: 74394

Gnomad4 AFR AF: 0.443

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.434

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.0821

Gnomad4 NFE AF: 0.0819

Gnomad4 OTH AF: 0.212

Alfa AF: 0.141 Hom.: 1508

Bravo AF: 0.224

Asia WGS AF: 0.323 AC: 1123 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inflammatory bowel disease 19 Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.646, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.53
Dann	Benign	0.53

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

LitVar

Other links and lift over

dbSNP: rs10065172; hg19: chr5-150227998; COSMIC: COSV72988781; COSMIC: COSV72988781;