chr14-104714295-C-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_022489.4(INF2):​c.3133C>T​(p.Arg1045Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,592,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. R1045Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

INF2
NM_022489.4 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.0430

Publications

2 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13847613).
BP6
Variant 14-104714295-C-T is Benign according to our data. Variant chr14-104714295-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472850.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
INF2NM_022489.4 linkc.3133C>T p.Arg1045Trp 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
INF2ENST00000392634.9 linkc.3133C>T p.Arg1045Trp missense_variant Exon 21 of 23 5 NM_022489.4 ENSP00000376410.4 Q27J81-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152172
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000381
AC:
8
AN:
210006
AF XY:
0.0000437
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000324
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000750
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000299
AC:
43
AN:
1439836
Hom.:
0
Cov.:
70
AF XY:
0.0000350
AC XY:
25
AN XY:
714582
show subpopulations
African (AFR)
AF:
0.0000304
AC:
1
AN:
32872
American (AMR)
AF:
0.0000238
AC:
1
AN:
41980
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25620
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38360
South Asian (SAS)
AF:
0.0000120
AC:
1
AN:
82990
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50088
Middle Eastern (MID)
AF:
0.000174
AC:
1
AN:
5736
European-Non Finnish (NFE)
AF:
0.0000345
AC:
38
AN:
1102620
Other (OTH)
AF:
0.0000168
AC:
1
AN:
59570
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000394
AC:
6
AN:
152172
Hom.:
0
Cov.:
34
AF XY:
0.0000269
AC XY:
2
AN XY:
74338
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41432
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000674
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000251
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Uncertain:1Benign:1
Aug 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 05, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nephrotic syndrome Uncertain:1
Oct 25, 2018
Sydney Genome Diagnostics, Children's Hospital Westmead
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This patient is heterozygous for a c.3133C>T (p.Arg1045Trp) in exon 21 of the INF2 gene. To our knowledge, this variant has not been previously reported. p.Arg1045 is a weakly conserved amino acid (considering 12 species) and there is a moderate physicochemical difference between the wild type arginine and the variant tryptophan. In silico analysis (Alamut Visual v2.4) is inconclusive regarding this variant. Align GVGD and Mutation Taster predict this variant to be benign whereas PolyPhen and SIFT predict it to be pathogenic. -

Inborn genetic diseases Benign:1
Dec 13, 2019
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.062
.;T;.
Eigen
Benign
-0.53
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.082
N
LIST_S2
Benign
0.69
T;T;T
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.14
T;T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Benign
0.34
N;N;.
PhyloP100
-0.043
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-2.2
N;N;.
REVEL
Benign
0.20
Sift
Uncertain
0.0070
D;D;.
Sift4G
Uncertain
0.018
D;D;D
Polyphen
0.99
D;D;.
Vest4
0.094
MVP
0.18
MPC
0.26
ClinPred
0.13
T
GERP RS
1.8
Varity_R
0.067
gMVP
0.12
Mutation Taster
=93/7
polymorphism

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

Other links and lift over

dbSNP: rs780428043; hg19: chr14-105180632; API