chr19-43592343-C-T

Variant names:

• chr19-43592343-C-T
• rs754397160
• NM_001007561.3:c.1555G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001007561.3(IRGQ):​c.1555G>A​(p.Gly519Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000363 in 1,571,742 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: IRGQ NM_001007561.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08831161).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRGQ	NM_001007561.3	c.1555G>A	p.Gly519Ser	missense_variant	Exon 3 of 3	ENST00000422989.6	NP_001007562.1
IRGQ	NM_001388309.1	c.1555G>A	p.Gly519Ser	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.1555G>A	p.Gly519Ser	missense_variant	Exon 3 of 3	5	NM_001007561.3	ENSP00000387535.1
IRGQ	ENST00000602269.2	c.1555G>A	p.Gly519Ser	missense_variant	Exon 2 of 2	1		ENSP00000472250.1
ENSG00000268361	ENST00000594374.1	c.168+525G>A		intron_variant	Intron 1 of 2	3		ENSP00000472698.1
IRGQ	ENST00000601520.1	n.251+414G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000168 AC: 3 AN: 178928 AF XY: 0.0000200

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000387

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000394 AC: 56 AN: 1419532 Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 30 AN XY: 704594

African (AFR) AF: 0.00 AC: 0 AN: 32434

American (AMR) AF: 0.00 AC: 0 AN: 41686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25620

East Asian (EAS) AF: 0.00 AC: 0 AN: 37368

South Asian (SAS) AF: 0.00 AC: 0 AN: 82982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.0000500 AC: 55 AN: 1099088

Other (OTH) AF: 0.0000169 AC: 1 AN: 59072

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41456

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1555G>A (p.G519S) alteration is located in exon 3 (coding exon 2) of the IRGQ gene. This alteration results from a G to A substitution at nucleotide position 1555, causing the glycine (G) at amino acid position 519 to be replaced by a serine (S). 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	0.090
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.78
DEOGEN2	Benign	0.0032	T;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.54	T;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.088	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.075	N;N
PhyloP100		1.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.82	N;.
REVEL	Benign	0.050
Sift	Benign	0.83	T;.
Sift4G	Benign	0.090	T;T
Polyphen		0.073	B;B
Vest4		0.070
MutPred		0.31		Gain of phosphorylation at G519 (P = 0.0259);Gain of phosphorylation at G519 (P = 0.0259);
MVP		0.35
ClinPred		0.086	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.089
gMVP		0.48
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs754397160; hg19: chr19-44096495;