Genetic Variant INF2:p.Arg1074Thr (chr14-104714383-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_022489.4(INF2):c.3221G>C(p.Arg1074Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R1074K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

INF2
NM_022489.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.42

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31110424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INF2	NM_022489.4 link	c.3221G>C	p.Arg1074Thr	missense_variant	Exon 21 of 23	ENST00000392634.9	NP_071934.3	Q27J81-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9 link	c.3221G>C	p.Arg1074Thr	missense_variant	Exon 21 of 23	5	NM_022489.4	ENSP00000376410.4		Q27J81-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448474

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719624

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33190

American (AMR)

AF:

0.00

AC:

AN:

42422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25864

East Asian (EAS)

AF:

0.00

AC:

AN:

39034

South Asian (SAS)

AF:

0.00

AC:

AN:

84464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51668

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106204

Other (OTH)

AF:

0.00

AC:

AN:

59884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.051

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.18

.;T;.

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

T;T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.1

L;L;.

PhyloP100

1.4

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.7

D;D;.

REVEL

Uncertain

0.41

Sift

Uncertain

0.014

D;D;.

Sift4G

Benign

0.11

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.48

MutPred

0.41

Gain of catalytic residue at L1072 (P = 2e-04);Gain of catalytic residue at L1072 (P = 2e-04);.;

MVP

0.67

MPC

0.36

ClinPred

0.85

GERP RS

4.1

Varity_R

0.22

gMVP

0.22

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over