Variant 7-128947398-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001098629.3(IRF5):c.650C>A(p.Ala217Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A217V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

IRF5
NM_001098629.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.805

Variant links:

Genes affected

IRF5 (HGNC:6120): (interferon regulatory factor 5) This gene encodes a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity. Members of the IRF family are characterized by a conserved N-terminal DNA-binding domain containing tryptophan (W) repeats. Alternative promoter use and alternative splicing result in multiple transcript variants, and a 30-nt indel polymorphism (SNP rs60344245) can result in loss of a 10-aa segment. [provided by RefSeq, Dec 2016]

IRF5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11427951).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF5	NM_001098629.3 linkuse as main transcript	c.650C>A	p.Ala217Asp	missense_variant	6/9	ENST00000357234.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF5	ENST00000357234.10 linkuse as main transcript	c.650C>A	p.Ala217Asp	missense_variant	6/9	1	NM_001098629.3		Q13568-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1458436

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725448

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2023

The c.650C>A (p.A217D) alteration is located in exon 6 (coding exon 5) of the IRF5 gene. This alteration results from a C to A substitution at nucleotide position 650, causing the alanine (A) at amino acid position 217 to be replaced by an aspartic acid (D). 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

0.12

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Benign

4.2

DANN

Benign

0.94

DEOGEN2

Benign

0.16

.;.;T;T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.61

.;T;.;T;.

M_CAP

Benign

0.080

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

.;.;L;L;L

MutationTaster

Benign

0.84

D;D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.42

.;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.31

.;T;T;T;T

Sift4G

Benign

0.23

.;T;T;T;T

Polyphen

0.34

B;B;B;B;B

Vest4

0.23, 0.24, 0.24, 0.25

MutPred

0.29

.;.;Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);

MVP

0.63

MPC

0.021

ClinPred

0.15

GERP RS

0.075

Varity_R

0.11

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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