5-150848502-C-T

Variant names:

• chr5-150848502-C-T
• rs1288606899
• NM_001145805.2:c.379C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145805.2(IRGM):​c.379C>T​(p.His127Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,551,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H127D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IRGM NM_001145805.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0680
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28533113).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145805.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRGM	NM_001145805.2	MANE Select	c.379C>T	p.His127Tyr	missense	Exon 2 of 2	NP_001139277.1	A1A4Y4-1
	IRGM	NM_001346557.2		c.379C>T	p.His127Tyr	missense	Exon 2 of 4	NP_001333486.1	A1A4Y4-2
	IRGM	NR_170598.1		n.1494C>T		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRGM	ENST00000522154.2	TSL:1 MANE Select	c.379C>T	p.His127Tyr	missense	Exon 2 of 2	ENSP00000428220.1	A1A4Y4-1
	IRGM	ENST00000520549.1	TSL:1	n.4C>T		non_coding_transcript_exon	Exon 1 of 4	ENSP00000429819.1	A0A9H4B933
	IRGM	ENST00000951736.1		c.379C>T	p.His127Tyr	missense	Exon 2 of 2	ENSP00000621795.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399526 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 690286

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35876

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078958

Other (OTH) AF: 0.0000172 AC: 1 AN: 58002

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.092
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.068
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.094
Sift	Uncertain	0.021	D
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.12
MutPred		0.65		Loss of catalytic residue at H127 (P = 0.0273)
MVP		0.030
ClinPred		0.77	D
GERP RS		3.0
Varity_R		0.25
gMVP		0.49
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1288606899; hg19: chr5-150228064; COSMIC: COSV107544571;