chr7-128946562-G-A

Variant names:

• chr7-128946562-G-A
• rs201418545
• NM_001098629.3:c.447G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001098629.3(IRF5):​c.447G>A​(p.Glu149Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,591,564 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: IRF5 NM_001098629.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9971
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0540

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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052229166).
• BP6: Variant 7-128946562-G-A is Benign according to our data. Variant chr7-128946562-G-A is described in ClinVar as [Benign]. Clinvar id is 709580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF5	NM_001098629.3	c.447G>A	p.Glu149Glu	splice_region_variant, synonymous_variant	Exon 4 of 9	ENST00000357234.10	NP_001092099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF5	ENST00000357234.10	c.447G>A	p.Glu149Glu	splice_region_variant, synonymous_variant	Exon 4 of 9	1	NM_001098629.3	ENSP00000349770.5

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00608

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00169 AC: 391 AN: 230856 AF XY: 0.00122

Gnomad AFR exome AF: 0.000137

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000359 AC: 516 AN: 1439240 Hom.: 4 Cov.: 26 AF XY: 0.000296 AC XY: 212 AN XY: 715560

Gnomad4 AFR exome AF: 0.0000302 AC: 1 AN: 33122

Gnomad4 AMR exome AF: 0.0114 AC: 487 AN: 42818

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25822

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39440

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 83760

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51240

Gnomad4 NFE exome AF: 0.00000364 AC: 4 AN: 1097520

Gnomad4 Remaining exome AF: 0.000401 AC: 24 AN: 59784

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000698 AC XY: 52 AN XY: 74484

Gnomad4 AFR AF: 0.000240 AC: 0.0002405 AN: 0.0002405

Gnomad4 AMR AF: 0.00601 AC: 0.0060115 AN: 0.0060115

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.000945 AC: 0.00094518 AN: 0.00094518

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.00146

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00120 AC: 145

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.97
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0052	T
Sift4G	Uncertain	0.0090	D
Vest4		0.25
MVP		0.33
GERP RS		3.6
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.040		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: rs201418545; hg19: chr7-128586616;