Genetic Variant INF2:p.Arg9Leu (chr14-104701391-G-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022489.4(INF2):c.26G>T(p.Arg9Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000748 in 1,590,604 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000072 ( 1 hom. )

Consequence

INF2
NM_022489.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.62

Publications

1 publications found

Variant links:

Genes affected

INF2 (HGNC:23791): (inverted formin 2) This gene represents a member of the formin family of proteins. It is considered a diaphanous formin due to the presence of a diaphanous inhibitory domain located at the N-terminus of the encoded protein. Studies of a similar mouse protein indicate that the protein encoded by this locus may function in polymerization and depolymerization of actin filaments. Mutations at this locus have been associated with focal segmental glomerulosclerosis 5.[provided by RefSeq, Aug 2010]

INF2 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease dominant intermediate E
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
focal segmental glomerulosclerosis 5
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

INF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009543747).

BP6

Variant 14-104701391-G-T is Benign according to our data. Variant chr14-104701391-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1903886.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000984 (15/152366) while in subpopulation SAS AF = 0.0031 (15/4834). AF 95% confidence interval is 0.00191. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022489.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INF2	NM_022489.4	MANE Select	c.26G>T	p.Arg9Leu	missense	Exon 2 of 23	NP_071934.3	Q27J81-1
INF2	NM_001426862.1		c.26G>T	p.Arg9Leu	missense	Exon 2 of 23	NP_001413791.1
INF2	NM_001426863.1		c.26G>T	p.Arg9Leu	missense	Exon 2 of 23	NP_001413792.1	Q27J81-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INF2	ENST00000392634.9	TSL:5 MANE Select	c.26G>T	p.Arg9Leu	missense	Exon 2 of 23	ENSP00000376410.4	Q27J81-1
INF2	ENST00000398337.8	TSL:1	c.26G>T	p.Arg9Leu	missense	Exon 2 of 5	ENSP00000381380.4	Q27J81-3
INF2	ENST00000617571.5	TSL:1	n.26G>T		non_coding_transcript_exon	Exon 1 of 22	ENSP00000483829.2	A0A087X118

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152248

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:

0.00310

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000110

AC:

AN:

209576

AF XY:

0.000183

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000723

AC:

104

AN:

1438238

Hom.:

Cov.:

AF XY:

0.0000925

AC XY:

AN XY:

713198

show subpopulations

African (AFR)

AF:

0.0000303

AC:

AN:

32968

American (AMR)

AF:

0.00

AC:

AN:

42590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25720

East Asian (EAS)

AF:

0.00

AC:

AN:

38428

South Asian (SAS)

AF:

0.00122

AC:

101

AN:

83086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5546

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100100

Other (OTH)

AF:

0.0000337

AC:

AN:

59354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000984

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41586

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00310

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000183

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.0095

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.0

PhyloP100

3.6

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.36

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.027

Polyphen

0.99

Vest4

0.36

MutPred

0.43

Gain of catalytic residue at R9 (P = 2e-04)

MVP

0.42

MPC

2.6

ClinPred

0.26

GERP RS

1.9

PromoterAI

0.0094

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.68

Mutation Taster

=71/29

polymorphism

(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