Genetic Variant IFRD1:c.568-3dupT (chr7-112461852-A-AT) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_ModeratePM2BP6

The NM_001550.4(IFRD1):c.568-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,180,932 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0020 ( 0 hom. )

Consequence

IFRD1
NM_001550.4 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.209

Variant links:

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]

IFRD1 links:

ENSG00000288640 (HGNC:):

ENSG00000288640 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03761062 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.7, offset of 0 (no position change), new splice context is: tatatattttttttttttAGtgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 7-112461852-A-AT is Benign according to our data. Variant chr7-112461852-A-AT is described in ClinVar as [Likely_benign]. Clinvar id is 3041772.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFRD1	NM_001550.4 link	c.568-3dupT		splice_acceptor_variant, intron_variant	Intron 5 of 11	ENST00000403825.8	NP_001541.2	O00458-1A4D0U1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFRD1	ENST00000403825.8 link	c.568-3dupT		splice_acceptor_variant, intron_variant	Intron 5 of 11	1	NM_001550.4	ENSP00000384477.3		O00458-1
ENSG00000288640	ENST00000676282.1 link	n.568-3dupT		splice_acceptor_variant, intron_variant	Intron 5 of 14			ENSP00000501830.1

Frequencies

GnomAD3 genomes

AF:

0.00000668

AC:

AN:

149798

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000100

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000924

AC:

142

AN:

153706

Hom.:

AF XY:

0.000872

AC XY:

AN XY:

83692

show subpopulations

Gnomad AFR exome

AF:

0.0000985

Gnomad AMR exome

AF:

0.00163

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00489

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.000133

Gnomad NFE exome

AF:

0.000490

Gnomad OTH exome

AF:

0.000519

GnomAD4 exome

AF:

0.00204

AC:

2100

AN:

1031134

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

991

AN XY:

523996

show subpopulations

Gnomad4 AFR exome

AF:

0.000762

Gnomad4 AMR exome

AF:

0.00155

Gnomad4 ASJ exome

AF:

0.000280

Gnomad4 EAS exome

AF:

0.00557

Gnomad4 SAS exome

AF:

0.00168

Gnomad4 FIN exome

AF:

0.000683

Gnomad4 NFE exome

AF:

0.00216

Gnomad4 OTH exome

AF:

0.00163

GnomAD4 genome

AF:

0.00000668

AC:

AN:

149798

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73030

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000100

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

IFRD1-related disorder

Benign:1

Mar 07, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Other links and lift over