14-104714221-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022489.4(INF2):​c.3059C>T​(p.Ala1020Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000846 in 1,547,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

INF2
NM_022489.4 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: -3.18
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.047522724).
BP6
Variant 14-104714221-C-T is Benign according to our data. Variant chr14-104714221-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540037.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000526 (8/152196) while in subpopulation NFE AF= 0.0000882 (6/68024). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
INF2NM_022489.4 linkuse as main transcriptc.3059C>T p.Ala1020Val missense_variant 21/23 ENST00000392634.9 NP_071934.3 Q27J81-1
INF2NM_001031714.4 linkuse as main transcriptc.3059C>T p.Ala1020Val missense_variant 21/22 NP_001026884.3 Q27J81-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
INF2ENST00000392634.9 linkuse as main transcriptc.3059C>T p.Ala1020Val missense_variant 21/235 NM_022489.4 ENSP00000376410.4 Q27J81-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152196
Hom.:
0
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000345
AC:
6
AN:
174068
Hom.:
0
AF XY:
0.0000321
AC XY:
3
AN XY:
93334
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000692
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000649
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000881
AC:
123
AN:
1395626
Hom.:
0
Cov.:
31
AF XY:
0.0000844
AC XY:
58
AN XY:
687510
show subpopulations
Gnomad4 AFR exome
AF:
0.0000623
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000268
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000110
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152196
Hom.:
0
Cov.:
35
AF XY:
0.0000404
AC XY:
3
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000529
ESP6500AA
AF:
0.000249
AC:
1
ESP6500EA
AF:
0.000121
AC:
1
ExAC
AF:
0.0000593
AC:
7

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 15, 2020The p.A1020V variant (also known as c.3059C>T), located in coding exon 20 of the INF2 gene, results from a C to T substitution at nucleotide position 3059. The alanine at codon 1020 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 20, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
4.5
DANN
Benign
0.84
DEOGEN2
Benign
0.025
.;T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.014
N
LIST_S2
Benign
0.56
T;T;T
M_CAP
Benign
0.079
D
MetaRNN
Benign
0.048
T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.0
N;N;.
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.62
N;N;.
REVEL
Benign
0.12
Sift
Benign
0.47
T;T;.
Sift4G
Benign
0.48
T;T;T
Polyphen
0.0010
B;B;.
Vest4
0.027
MVP
0.31
MPC
0.25
ClinPred
0.027
T
GERP RS
-5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.035
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368372551; hg19: chr14-105180558; API