rs530391015
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_022489.4(INF2):c.658G>A(p.Glu220Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
INF2
NM_022489.4 missense
NM_022489.4 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 7.67
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_022489.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975
PP5
Variant 14-104703445-G-A is Pathogenic according to our data. Variant chr14-104703445-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104703445-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INF2 | NM_022489.4 | c.658G>A | p.Glu220Lys | missense_variant | 4/23 | ENST00000392634.9 | |
INF2 | NM_001031714.4 | c.658G>A | p.Glu220Lys | missense_variant | 4/22 | ||
INF2 | NM_032714.3 | c.658G>A | p.Glu220Lys | missense_variant | 4/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INF2 | ENST00000392634.9 | c.658G>A | p.Glu220Lys | missense_variant | 4/23 | 5 | NM_022489.4 | P4 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459720Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 726212
GnomAD4 exome
AF:
AC:
1
AN:
1459720
Hom.:
Cov.:
34
AF XY:
AC XY:
0
AN XY:
726212
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Focal segmental glomerulosclerosis 5 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 02, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Sep 14, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 14, 2022 | - - |
Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 04, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 220 of the INF2 protein (p.Glu220Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dominant focal segmental glomerulosclerosis (PMID: 20023659, 21258034, 23515051). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 523533). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt INF2 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2022 | - - |
Charcot-Marie-Tooth disease dominant intermediate E Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Sep 08, 2021 | - - |
Focal segmental glomerulosclerosis;C0020538:Hypertensive disorder;C0033687:Proteinuria;C1565489:Renal insufficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 17, 2022 | This variant has been identified in multiple individuals with focal segmental glomerulosclerosis and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;D
Vest4
MutPred
Gain of catalytic residue at L224 (P = 7e-04);Gain of catalytic residue at L224 (P = 7e-04);Gain of catalytic residue at L224 (P = 7e-04);
MVP
MPC
2.6
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at