Genetic Variant IRGQ:p.His546Arg (chr19-43592261-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001007561.3(IRGQ):c.1637A>G(p.His546Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,423,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

IRGQ
NM_001007561.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.23

Publications

0 publications found

Variant links:

Genes affected

IRGQ (HGNC:24868): (immunity related GTPase Q) Predicted to enable GTP binding activity. [provided by Alliance of Genome Resources, Apr 2022]

IRGQ links:

ENSG00000268361 (HGNC:):

ENSG00000268361 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.032424837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRGQ	NM_001007561.3 link	c.1637A>G	p.His546Arg	missense_variant	Exon 3 of 3	ENST00000422989.6	NP_001007562.1	Q8WZA9
IRGQ	NM_001388309.1 link	c.1637A>G	p.His546Arg	missense_variant	Exon 3 of 3		NP_001375238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRGQ	ENST00000422989.6 link	c.1637A>G	p.His546Arg	missense_variant	Exon 3 of 3	5	NM_001007561.3	ENSP00000387535.1	Q8WZA9
IRGQ	ENST00000602269.2 link	c.1637A>G	p.His546Arg	missense_variant	Exon 2 of 2	1		ENSP00000472250.1	Q8WZA9
ENSG00000268361	ENST00000594374.1 link	c.168+607A>G		intron_variant	Intron 1 of 2	3		ENSP00000472698.1	M0R2N6
IRGQ	ENST00000601520.1 link	n.251+496A>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1423836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32608

American (AMR)

AF:

0.00

AC:

AN:

41404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25654

East Asian (EAS)

AF:

0.00

AC:

AN:

37668

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101156

Other (OTH)

AF:

0.00

AC:

AN:

59228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1637A>G (p.H546R) alteration is located in exon 3 (coding exon 2) of the IRGQ gene. This alteration results from a A to G substitution at nucleotide position 1637, causing the histidine (H) at amino acid position 546 to be replaced by an arginine (R). 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

0.061

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.34

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.0029

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0090

LIST_S2

Benign

0.33

T;.

M_CAP

Benign

0.013

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PhyloP100

-1.2

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.81

N;.

REVEL

Benign

0.0060

Sift

Benign

0.87

T;.

Sift4G

Benign

0.67

T;T

Polyphen

0.0

B;B

Vest4

0.030

MutPred

0.31

Gain of methylation at H546 (P = 0.0186);Gain of methylation at H546 (P = 0.0186);

MVP

0.20

ClinPred

0.016

GERP RS

-6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.025

gMVP

0.38

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over