5-150848436-C-T

Variant names:

• chr5-150848436-C-T
• rs10065172
• NM_001145805.2:c.313C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001145805.2(IRGM):​c.313C>T​(p.Leu105Leu) 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
• Publications: 123 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-150848436-C-T is Benign according to our data. Variant chr5-150848436-C-T is described in ClinVar as Benign. ClinVar VariationId is 30716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
IRGM	NM_001145805.2	c.313C>T	p.Leu105Leu	synonymous_variant	Exon 2 of 2	ENST00000522154.2	NP_001139277.1
IRGM	NM_001346557.2	c.313C>T	p.Leu105Leu	synonymous_variant	Exon 2 of 4		NP_001333486.1
IRGM	NR_170598.1	n.1428C>T		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	c.313C>T	p.Leu105Leu	synonymous_variant	Exon 2 of 2	1	NM_001145805.2	ENSP00000428220.1
IRGM	ENST00000520549.1	n.-63C>T		upstream_gene_variant		1		ENSP00000429819.1

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

GnomAD2 exomes AF: 0.165 AC: 25447 AN: 154216 AF XY: 0.164

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 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

African (AFR) AF: 0.454 AC: 14344 AN: 31594

American (AMR) AF: 0.144 AC: 5144 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4281 AN: 25180

East Asian (EAS) AF: 0.389 AC: 13938 AN: 35874

South Asian (SAS) AF: 0.200 AC: 15828 AN: 79234

European-Finnish (FIN) AF: 0.0839 AC: 4135 AN: 49278

Middle Eastern (MID) AF: 0.246 AC: 1402 AN: 5698

European-Non Finnish (NFE) AF: 0.0790 AC: 85233 AN: 1078884

Other (OTH) AF: 0.153 AC: 8850 AN: 57994

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

African (AFR) AF: 0.443 AC: 18360 AN: 41464

American (AMR) AF: 0.154 AC: 2359 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 569 AN: 3472

East Asian (EAS) AF: 0.434 AC: 2246 AN: 5176

South Asian (SAS) AF: 0.211 AC: 1016 AN: 4812

European-Finnish (FIN) AF: 0.0821 AC: 871 AN: 10614

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.0819 AC: 5572 AN: 68014

Other (OTH) AF: 0.212 AC: 448 AN: 2112

Alfa AF: 0.149 Hom.: 2144

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

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Benign:1

Oct 28, 2020

H3Africa Consortium

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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
PhyloP100		0.66
Mutation Taster		=100/0	disease causing (ClinVar)

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