19-43592703-C-A

Variant names:

• chr19-43592703-C-A
• rs111946192
• NM_001007561.3:c.1195G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001007561.3(IRGQ):​c.1195G>T​(p.Gly399Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,609,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: IRGQ NM_001007561.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.589
• Publications: 3 publications found

Genes affected

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

ENSG00000268361 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.09571841).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRGQ	NM_001007561.3	c.1195G>T	p.Gly399Cys	missense_variant	Exon 3 of 3	ENST00000422989.6	NP_001007562.1
IRGQ	NM_001388309.1	c.1195G>T	p.Gly399Cys	missense_variant	Exon 3 of 3		NP_001375238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRGQ	ENST00000422989.6	c.1195G>T	p.Gly399Cys	missense_variant	Exon 3 of 3	5	NM_001007561.3	ENSP00000387535.1
IRGQ	ENST00000602269.2	c.1195G>T	p.Gly399Cys	missense_variant	Exon 2 of 2	1		ENSP00000472250.1
ENSG00000268361	ENST00000594374.1	c.168+165G>T		intron_variant	Intron 1 of 2	3		ENSP00000472698.1
IRGQ	ENST00000601520.1	n.251+54G>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

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

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248490 AF XY: 0.0000223

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1456940 Hom.: 0 Cov.: 32 AF XY: 0.0000207 AC XY: 15 AN XY: 725074

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111976

Other (OTH) AF: 0.0000828 AC: 5 AN: 60374

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74492

African (AFR) AF: 0.000313 AC: 13 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000761 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1195G>T (p.G399C) alteration is located in exon 3 (coding exon 2) of the IRGQ gene. This alteration results from a G to T substitution at nucleotide position 1195, causing the glycine (G) at amino acid position 399 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	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.43	T;.
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	2.0	M;M
PhyloP100		-0.59
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.23	N;.
REVEL	Benign	0.16
Sift	Benign	0.067	T;.
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;D
Vest4		0.20
MVP		0.67
ClinPred		0.31	T
GERP RS		1.1
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.078
gMVP		0.57
Mutation Taster		=96/4	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: rs111946192; hg19: chr19-44096855;