Genetic Variant INF2:p.Arg1045Leu (chr14-104714296-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022489.4(INF2):c.3134G>T(p.Arg1045Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1045W) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

INF2
NM_022489.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.22

Publications

4 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049812853).

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
INF2	NM_022489.4	MANE Select	c.3134G>T	p.Arg1045Leu	missense	Exon 21 of 23	NP_071934.3
INF2	NM_001426862.1		c.3134G>T	p.Arg1045Leu	missense	Exon 21 of 23	NP_001413791.1
INF2	NM_001426863.1		c.3134G>T	p.Arg1045Leu	missense	Exon 21 of 23	NP_001413792.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INF2	ENST00000392634.9	TSL:5 MANE Select	c.3134G>T	p.Arg1045Leu	missense	Exon 21 of 23	ENSP00000376410.4
INF2	ENST00000617571.5	TSL:1	n.3130G>T		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2
INF2	ENST00000675207.1		c.3230G>T	p.Arg1077Leu	missense	Exon 21 of 23	ENSP00000502644.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1439634

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714468

African (AFR)

AF:

0.00

AC:

AN:

32870

American (AMR)

AF:

0.00

AC:

AN:

41952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25628

East Asian (EAS)

AF:

0.00

AC:

AN:

38352

South Asian (SAS)

AF:

0.00

AC:

AN:

82948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102534

Other (OTH)

AF:

0.00

AC:

AN:

59582

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000835

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.0050

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.054

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.56

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.34

PhyloP100

-3.2

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.9

REVEL

Benign

0.15

Sift

Benign

0.045

Sift4G

Benign

0.26

Polyphen

0.0010

Vest4

0.11

MutPred

0.30

Gain of catalytic residue at R1045 (P = 0)

MVP

0.13

MPC

0.31

ClinPred

0.085

GERP RS

-7.4

Varity_R

0.064

gMVP

0.11

Mutation Taster

=95/5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over