7-112461996-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001550.4(IFRD1):c.619-5A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,609,074 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (29 hom.)
• Consequence: IFRD1 NM_001550.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002821
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.10

Genes affected

IFRD1 (HGNC:5456): (interferon related developmental regulator 1) This gene is an immediate early gene that encodes a protein related to interferon-gamma. This protein may function as a transcriptional co-activator/repressor that controls the growth and differentiation of specific cell types during embryonic development and tissue regeneration. Mutations in this gene are associated with sensory/motor neuropathy with ataxia. This gene may also be involved in modulating the pathogenesis of cystic fibrosis lung disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-112461996-A-G is Benign according to our data. Variant chr7-112461996-A-G is described in ClinVar as [Benign]. Clinvar id is 713158.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-112461996-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFRD1	NM_001550.4	c.619-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000403825.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFRD1	ENST00000403825.8	c.619-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001550.4	P3

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152086 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00268 AC: 672 AN: 250596 Hom.: 5 AF XY: 0.00334 AC XY: 452 AN XY: 135450

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00527

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0110

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00232 AC: 3381 AN: 1456870 Hom.: 29 Cov.: 32 AF XY: 0.00270 AC XY: 1957 AN XY: 725162

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000806

Gnomad4 ASJ exome AF: 0.00441

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.000469

Gnomad4 NFE exome AF: 0.00179

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152204 Hom.: 4 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74420

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00173 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.00218

EpiControl AF: 0.00314

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	3.7
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.050		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: rs201937029; hg19: chr7-112102051;