chr11-614243-C-A

Variant names:

• chr11-614243-C-A
• rs41313489
• NM_001572.5:c.610G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001572.5(IRF7):​c.610G>T​(p.Asp204Tyr) 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. 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. D204N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF7 NM_001572.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.533
• Publications: 8 publications found

Genes affected

IRF7 (HGNC:6122): (interferon regulatory factor 7) This gene encodes interferon regulatory factor 7, a member of the interferon regulatory transcription factor (IRF) family. It has been shown to play a role in the transcriptional activation of virus-inducible cellular genes, including interferon beta chain genes. Inducible expression of IRF7 is largely restricted to lymphoid tissue. The encoded protein plays an important role in the innate immune response against DNA and RNA viruses. [provided by RefSeq, Jul 2021]

IRF7 Gene-Disease associations (from GenCC):

• immunodeficiency 39

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21306384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF7	NM_001572.5	c.610G>T	p.Asp204Tyr	missense_variant	Exon 6 of 11	ENST00000525445.6	NP_001563.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF7	ENST00000525445.6	c.610G>T	p.Asp204Tyr	missense_variant	Exon 6 of 11	5	NM_001572.5	ENSP00000434009.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 39 Uncertain:1

Aug 06, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces aspartic acid with tyrosine at codon 217 of the IRF7 protein (p.Asp217Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with IRF7-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.16	T;.;.;T;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.79	.;T;T;T;T;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.9	L;.;L;L;.;.
PhyloP100		0.53
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.7	D;D;D;.;.;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.010	D;D;T;.;.;D
Sift4G	Uncertain	0.026	D;D;T;.;T;D
Polyphen		0.36	B;B;D;B;.;B
Vest4		0.24
MutPred		0.37		Loss of disorder (P = 0.0107);.;Loss of disorder (P = 0.0107);Loss of disorder (P = 0.0107);.;.;
MVP		0.74
MPC		0.26
ClinPred		0.95	D
GERP RS		1.3
Varity_R		0.21
gMVP		0.40
Mutation Taster		=86/14	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: rs41313489; hg19: chr11-614243;