chr19-43592256-G-A

Variant names:

• chr19-43592256-G-A
• rs780969464
• NM_001007561.3:c.1642C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001007561.3(IRGQ):​c.1642C>T​(p.Pro548Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000444 in 1,577,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: IRGQ NM_001007561.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34602517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRGQ	NM_001007561.3	c.1642C>T	p.Pro548Ser	missense_variant	Exon 3 of 3	ENST00000422989.6	NP_001007562.1
IRGQ	NM_001388309.1	c.1642C>T	p.Pro548Ser	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.1642C>T	p.Pro548Ser	missense_variant	Exon 3 of 3	5	NM_001007561.3	ENSP00000387535.1
IRGQ	ENST00000602269.2	c.1642C>T	p.Pro548Ser	missense_variant	Exon 2 of 2	1		ENSP00000472250.1
ENSG00000268361	ENST00000594374.1	c.168+612C>T		intron_variant	Intron 1 of 2	3		ENSP00000472698.1
IRGQ	ENST00000601520.1	n.251+501C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1424880 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 707844

African (AFR) AF: 0.00 AC: 0 AN: 32632

American (AMR) AF: 0.0000482 AC: 2 AN: 41474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25684

East Asian (EAS) AF: 0.00 AC: 0 AN: 37740

South Asian (SAS) AF: 0.00 AC: 0 AN: 83982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101718

Other (OTH) AF: 0.00 AC: 0 AN: 59238

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15306

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: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1642C>T (p.P548S) alteration is located in exon 3 (coding exon 2) of the IRGQ gene. This alteration results from a C to T substitution at nucleotide position 1642, causing the proline (P) at amino acid position 548 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	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.65	T;.
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		2.2
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.13
Sift	Benign	0.061	T;.
Sift4G	Benign	0.48	T;T
Polyphen		1.0	D;D
Vest4		0.29
MutPred		0.30		Gain of glycosylation at P548 (P = 0.0054);Gain of glycosylation at P548 (P = 0.0054);
MVP		0.67
ClinPred		0.88	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.098
gMVP		0.61
Mutation Taster		=82/18	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: rs780969464; hg19: chr19-44096408;