rs121912469

Positions:

• chr5-132489457-T-A
• chr5-132489457-T-C
• chr5-132489457-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_002198.3(IRF1):​c.22A>T​(p.Met8Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF1 NM_002198.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.07

Genes affected

IRF1 (HGNC:6116): (interferon regulatory factor 1) The protein encoded by this gene is a transcriptional regulator and tumor suppressor, serving as an activator of genes involved in both innate and acquired immune responses. The encoded protein activates the transcription of genes involved in the body's response to viruses and bacteria, playing a role in cell proliferation, apoptosis, the immune response, and DNA damage response. This protein represses the transcription of several other genes. As a tumor suppressor, it both suppresses tumor cell growth and stimulates an immune response against tumor cells. Defects in this gene have been associated with gastric cancer, myelogenous leukemia, and lung cancer. [provided by RefSeq, Aug 2017]

ENSG00000283782 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-132489457-T-A is Pathogenic according to our data. Variant chr5-132489457-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 14720.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF1	NM_002198.3	c.22A>T	p.Met8Leu	missense_variant	2/10	ENST00000245414.9	NP_002189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF1	ENST00000245414.9	c.22A>T	p.Met8Leu	missense_variant	2/10	1	NM_002198.3	ENSP00000245414.4
ENSG00000283782	ENST00000640655.2	c.-169+2797T>A		intron_variant		5		ENSP00000491596.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 12, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.82	D;D;D;.;D;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.90	L;L;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;D;.;D;D;.
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;.;T;T;.
Sift4G	Pathogenic	0.0	D;D;T;T;.;.
Polyphen		0.035	B;B;.;.;.;.
Vest4		0.65
MutPred		0.62		Gain of catalytic residue at M8 (P = 0.0392);Gain of catalytic residue at M8 (P = 0.0392);Gain of catalytic residue at M8 (P = 0.0392);Gain of catalytic residue at M8 (P = 0.0392);Gain of catalytic residue at M8 (P = 0.0392);Gain of catalytic residue at M8 (P = 0.0392);
MVP		0.90
MPC		1.7
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs121912469; hg19: chr5-131825149;