19-43592619-C-A

Position:

• chr19-43592619-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001007561.3(IRGQ):​c.1279G>T​(p.Ala427Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 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)
• Consequence: IRGQ NM_001007561.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.231

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05819705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRGQ	NM_001007561.3	c.1279G>T	p.Ala427Ser	missense_variant	3/3	ENST00000422989.6	NP_001007562.1
IRGQ	NM_001388309.1	c.1279G>T	p.Ala427Ser	missense_variant	3/3		NP_001375238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRGQ	ENST00000422989.6	c.1279G>T	p.Ala427Ser	missense_variant	3/3	5	NM_001007561.3	ENSP00000387535.1
IRGQ	ENST00000602269.2	c.1279G>T	p.Ala427Ser	missense_variant	2/2	1		ENSP00000472250.1
ENSG00000268361	ENST00000594374.1	c.168+249G>T		intron_variant		3		ENSP00000472698.1
IRGQ	ENST00000601520.1	n.251+138G>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000415 AC: 1 AN: 241164 Hom.: 0 AF XY: 0.00000761 AC XY: 1 AN XY: 131380

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2024

The c.1279G>T (p.A427S) 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 1279, causing the alanine (A) at amino acid position 427 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	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.5
DANN	Benign	0.88
DEOGEN2	Benign	0.0061	T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.53	T;.
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.10	N;.
REVEL	Benign	0.028
Sift	Benign	0.26	T;.
Sift4G	Benign	0.27	T;T
Polyphen		0.0020	B;B
Vest4		0.18
MutPred		0.23		Gain of glycosylation at A427 (P = 0.0019);Gain of glycosylation at A427 (P = 0.0019);
MVP		0.34
ClinPred		0.037	T
GERP RS		-0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.0
Varity_R		0.049
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs767833187; hg19: chr19-44096771;