19-43592495-C-T

Variant names:

• chr19-43592495-C-T
• rs764363953
• NM_001007561.3:c.1403G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001007561.3(IRGQ):​c.1403G>A​(p.Ser468Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000376 in 1,594,218 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: IRGQ NM_001007561.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.47
• Publications: 1 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054004014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRGQ	NM_001007561.3	c.1403G>A	p.Ser468Asn	missense_variant	Exon 3 of 3	ENST00000422989.6	NP_001007562.1
IRGQ	NM_001388309.1	c.1403G>A	p.Ser468Asn	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.1403G>A	p.Ser468Asn	missense_variant	Exon 3 of 3	5	NM_001007561.3	ENSP00000387535.1
IRGQ	ENST00000602269.2	c.1403G>A	p.Ser468Asn	missense_variant	Exon 2 of 2	1		ENSP00000472250.1
ENSG00000268361	ENST00000594374.1	c.168+373G>A		intron_variant	Intron 1 of 2	3		ENSP00000472698.1
IRGQ	ENST00000601520.1	n.251+262G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152176 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000184 AC: 4 AN: 217200 AF XY: 0.0000248

Gnomad AFR exome AF: 0.0000779

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: 0.0000306

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000402 AC: 58 AN: 1442042 Hom.: 0 Cov.: 32 AF XY: 0.0000418 AC XY: 30 AN XY: 717618

African (AFR) AF: 0.0000300 AC: 1 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 85898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5308

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1110004

Other (OTH) AF: 0.0000334 AC: 2 AN: 59944

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1403G>A (p.S468N) 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 1403, causing the serine (S) at amino acid position 468 to be replaced by an asparagine (N). 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	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.12
DANN	Benign	0.76
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.42	T;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;N
PhyloP100		-1.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.94	N;.
REVEL	Benign	0.0060
Sift	Benign	0.13	T;.
Sift4G	Benign	0.39	T;T
Polyphen		0.020	B;B
Vest4		0.11
MutPred		0.23		Loss of glycosylation at S468 (P = 0.0042);Loss of glycosylation at S468 (P = 0.0042);
MVP		0.22
ClinPred		0.015	T
GERP RS		-2.0
Varity_R		0.055
gMVP		0.27
Mutation Taster		=100/0	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: rs764363953; hg19: chr19-44096647;