chr5-132486363-T-C

Variant names:

• chr5-132486363-T-C
• rs9282762
• NM_002198.3:c.555A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_002198.3(IRF1):​c.555A>G​(p.Pro185Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 1,611,130 control chromosomes in the GnomAD database, including 97,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (11290 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86115 hom.)
• Consequence: IRF1 NM_002198.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.11
• Publications: 27 publications found

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]

CARINH (HGNC:33838): (colitis associated IRF1 antisense regulator of intestinal homeostasis)

ENSG00000283782 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-132486363-T-C is Benign according to our data. Variant chr5-132486363-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688380.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF1	NM_002198.3	c.555A>G	p.Pro185Pro	synonymous_variant	Exon 7 of 10	ENST00000245414.9	NP_002189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF1	ENST00000245414.9	c.555A>G	p.Pro185Pro	synonymous_variant	Exon 7 of 10	1	NM_002198.3	ENSP00000245414.4
ENSG00000283782	ENST00000638452.2	c.-169+36674T>C		intron_variant	Intron 3 of 26	5		ENSP00000492349.2

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57543 AN: 151918 Hom.: 11276 Cov.: 32

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.343

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.360

GnomAD2 exomes AF: 0.348 AC: 86806 AN: 249370 AF XY: 0.348

Gnomad AFR exome AF: 0.486

Gnomad AMR exome AF: 0.327

Gnomad ASJ exome AF: 0.317

Gnomad EAS exome AF: 0.345

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.330

Gnomad OTH exome AF: 0.357

GnomAD4 exome AF: 0.341 AC: 497978 AN: 1459094 Hom.: 86115 Cov.: 39 AF XY: 0.342 AC XY: 248267 AN XY: 725888

African (AFR) AF: 0.491 AC: 16442 AN: 33460

American (AMR) AF: 0.331 AC: 14820 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 8254 AN: 26130

East Asian (EAS) AF: 0.331 AC: 13118 AN: 39688

South Asian (SAS) AF: 0.387 AC: 33373 AN: 86238

European-Finnish (FIN) AF: 0.327 AC: 16738 AN: 51188

Middle Eastern (MID) AF: 0.404 AC: 2330 AN: 5766

European-Non Finnish (NFE) AF: 0.335 AC: 371828 AN: 1111544

Other (OTH) AF: 0.349 AC: 21075 AN: 60358

GnomAD4 genome AF: 0.379 AC: 57600 AN: 152036 Hom.: 11290 Cov.: 32 AF XY: 0.378 AC XY: 28098 AN XY: 74330

African (AFR) AF: 0.487 AC: 20169 AN: 41420

American (AMR) AF: 0.343 AC: 5250 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1122 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1859 AN: 5162

South Asian (SAS) AF: 0.409 AC: 1972 AN: 4816

European-Finnish (FIN) AF: 0.329 AC: 3479 AN: 10578

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22636 AN: 67966

Other (OTH) AF: 0.360 AC: 762 AN: 2114

Alfa AF: 0.342 Hom.: 3564

Bravo AF: 0.382

Asia WGS AF: 0.377 AC: 1311 AN: 3478

EpiCase AF: 0.329

EpiControl AF: 0.325

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 66% of patients studied by a panel of primary immunodeficiencies. Number of patients: 58. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.066
DANN	Benign	0.48
PhyloP100		-5.1
PromoterAI		-0.0054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs9282762; hg19: chr5-131822055; COSMIC: COSV55377461; COSMIC: COSV55377461;