dbSNP rs978814079: IRGM:p.Tyr78Cys (chr5-150848356-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001145805.2(IRGM):c.233A>G(p.Tyr78Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,551,536 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

IRGM
NM_001145805.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.45

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRGM	NM_001145805.2 link	c.233A>G	p.Tyr78Cys	missense_variant	Exon 2 of 2	ENST00000522154.2	NP_001139277.1	A1A4Y4-1
IRGM	NM_001346557.2 link	c.233A>G	p.Tyr78Cys	missense_variant	Exon 2 of 4		NP_001333486.1	A1A4Y4-2
IRGM	NR_170598.1 link	n.1348A>G		non_coding_transcript_exon_variant	Exon 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRGM	ENST00000522154.2 link	c.233A>G	p.Tyr78Cys	missense_variant	Exon 2 of 2	1	NM_001145805.2	ENSP00000428220.1		A1A4Y4-1
IRGM	ENST00000520549.1 link	n.-143A>G		upstream_gene_variant		1		ENSP00000429819.1		A0A9H4B933

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD3 exomes

AF:

0.0000324

AC:

AN:

154268

Hom.:

AF XY:

0.0000367

AC XY:

AN XY:

81850

show subpopulations

Gnomad AFR exome

AF:

0.000632

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000264

AC:

AN:

1399532

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

690280

show subpopulations

Gnomad4 AFR exome

AF:

0.000285

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000167

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.000132

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.233A>G (p.Y78C) alteration is located in exon 2 (coding exon 1) of the IRGM gene. This alteration results from a A to G substitution at nucleotide position 233, causing the tyrosine (Y) at amino acid position 78 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.65

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.66

MutationAssessor

Pathogenic

3.5

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-8.0

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.47

MVP

0.18

ClinPred

0.70

GERP RS

3.8

Varity_R

0.83

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over