Genetic Variant NM_001550.4:c.634C>G (chr7-112462016-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001550.4(IFRD1):c.634C>G(p.Leu212Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,612,418 control chromosomes in the GnomAD database, including 66 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 57 hom. )

Consequence

IFRD1
NM_001550.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.48

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 18
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

IFRD1 links:

ENSG00000288640 (HGNC:):

ENSG00000288640 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065864623).

BP6

Variant 7-112462016-C-G is Benign according to our data. Variant chr7-112462016-C-G is described in ClinVar as Benign. ClinVar VariationId is 218480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00177 (2591/1460266) while in subpopulation AMR AF = 0.0406 (1813/44654). AF 95% confidence interval is 0.039. There are 57 homozygotes in GnomAdExome4. There are 1111 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 399 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001550.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IFRD1	NM_001550.4	MANE Select	c.634C>G	p.Leu212Val	missense	Exon 7 of 12	NP_001541.2	O00458-1
IFRD1	NM_001007245.3		c.634C>G	p.Leu212Val	missense	Exon 8 of 13	NP_001007246.1	O00458-1
IFRD1	NM_001197079.2		c.484C>G	p.Leu162Val	missense	Exon 7 of 12	NP_001184008.1	O00458-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IFRD1	ENST00000403825.8	TSL:1 MANE Select	c.634C>G	p.Leu212Val	missense	Exon 7 of 12	ENSP00000384477.3	O00458-1
IFRD1	ENST00000005558.8	TSL:1	c.634C>G	p.Leu212Val	missense	Exon 8 of 13	ENSP00000005558.4	O00458-1
ENSG00000288640	ENST00000676282.1		n.634C>G		non_coding_transcript_exon	Exon 7 of 15	ENSP00000501830.1

Frequencies

GnomAD3 genomes

AF:

0.00258

AC:

392

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00397

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00720

AC:

1805

AN:

250656

AF XY:

0.00551

show subpopulations

Gnomad AFR exome

AF:

0.000924

Gnomad AMR exome

AF:

0.0444

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00430

Gnomad FIN exome

AF:

0.00412

Gnomad NFE exome

AF:

0.000309

Gnomad OTH exome

AF:

0.00508

GnomAD4 exome

AF:

0.00177

AC:

2591

AN:

1460266

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

1111

AN XY:

726538

show subpopulations

African (AFR)

AF:

0.000449

AC:

AN:

33424

American (AMR)

AF:

0.0406

AC:

1813

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00671

AC:

266

AN:

39664

South Asian (SAS)

AF:

0.000812

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00328

AC:

175

AN:

53298

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000129

AC:

143

AN:

1110802

Other (OTH)

AF:

0.00179

AC:

108

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

139

278

418

557

696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00262

AC:

399

AN:

152152

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

212

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41506

American (AMR)

AF:

0.0163

AC:

249

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00444

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00397

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000954

Hom.:

Bravo

AF:

0.00447

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00595

AC:

722

Asia WGS

AF:

0.00462

AC:

AN:

3474

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

PhyloP100

2.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.84

REVEL

Benign

0.093

Sift

Benign

0.24

Sift4G

Benign

0.16

Polyphen

0.12

Vest4

0.41

MVP

0.62

MPC

0.71

ClinPred

0.013

GERP RS

2.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.089

gMVP

0.50

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over