rs72553867

chr5-150848404-C-Achr5-150848404-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001145805.2(IRGM):c.281C>A(p.Thr94Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,551,828 control chromosomes in the GnomAD database, including 2,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.039 (192 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1836 hom.)
• Consequence: IRGM NM_001145805.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002975881).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRGM	NM_001145805.2	c.281C>A	p.Thr94Lys	missense_variant	2/2	ENST00000522154.2
IRGM	NM_001346557.2	c.281C>A	p.Thr94Lys	missense_variant	2/4
IRGM	NR_170598.1	n.1396C>A		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRGM	ENST00000522154.2	c.281C>A	p.Thr94Lys	missense_variant	2/2	1	NM_001145805.2	P1

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5924 AN: 152200 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.0625

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0426

Gnomad OTH AF: 0.0388

GnomAD3 exomes AF: 0.0487 AC: 7518 AN: 154238 Hom.: 346 AF XY: 0.0503 AC XY: 4120 AN XY: 81832

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.182

Gnomad SAS exome AF: 0.0624

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0417

Gnomad OTH exome AF: 0.0432

GnomAD4 exome AF: 0.0447 AC: 62621 AN: 1399512 Hom.: 1836 Cov.: 33 AF XY: 0.0453 AC XY: 31300 AN XY: 690276

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.0206

Gnomad4 ASJ exome AF: 0.0399

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.0618

Gnomad4 FIN exome AF: 0.0293

Gnomad4 NFE exome AF: 0.0419

Gnomad4 OTH exome AF: 0.0464

GnomAD4 genome AF: 0.0389 AC: 5918 AN: 152316 Hom.: 192 Cov.: 32 AF XY: 0.0404 AC XY: 3007 AN XY: 74478

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0306

Gnomad4 ASJ AF: 0.0372

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.0626

Gnomad4 FIN AF: 0.0327

Gnomad4 NFE AF: 0.0426

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0438 Hom.: 331

Bravo AF: 0.0395

TwinsUK AF: 0.0369 AC: 137

ALSPAC AF: 0.0467 AC: 180

ESP6500AA AF: 0.0137 AC: 19

ESP6500EA AF: 0.0402 AC: 128

ExAC AF: 0.0437 AC: 1018

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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.91
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.052	T
Polyphen		0.99	D
Vest4		0.056
ClinPred		0.071	T
GERP RS		-4.0
Varity_R		0.66
gMVP		0.27

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: rs72553867; hg19: chr5-150227966; COSMIC: COSV72988817; COSMIC: COSV72988817;