14-104714242-C-T

Position:

chr14-104714242-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_022489.4(INF2):c.3080C>T(p.Thr1027Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,572,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

INF2
NM_022489.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.634

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0984942).

BP6

Variant 14-104714242-C-T is Benign according to our data. Variant chr14-104714242-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447577.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INF2	NM_022489.4 linkuse as main transcript	c.3080C>T	p.Thr1027Met	missense_variant	21/23	ENST00000392634.9	NP_071934.3
INF2	NM_001031714.4 linkuse as main transcript	c.3080C>T	p.Thr1027Met	missense_variant	21/22		NP_001026884.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9 linkuse as main transcript	c.3080C>T	p.Thr1027Met	missense_variant	21/23	5	NM_022489.4	ENSP00000376410	P4	Q27J81-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000313

AC:

AN:

191562

Hom.:

AF XY:

0.0000480

AC XY:

AN XY:

104176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000333

Gnomad ASJ exome

AF:

0.000126

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000417

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000358

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000197

AC:

AN:

1420530

Hom.:

Cov.:

AF XY:

0.0000228

AC XY:

AN XY:

703222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000487

Gnomad4 ASJ exome

AF:

0.0000409

Gnomad4 EAS exome

AF:

0.0000796

Gnomad4 SAS exome

AF:

0.0000249

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000165

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000843

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 06, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2023

The c.3080C>T (p.T1027M) alteration is located in exon 21 (coding exon 20) of the INF2 gene. This alteration results from a C to T substitution at nucleotide position 3080, causing the threonine (T) at amino acid position 1027 to be replaced by a methionine (M). This amino acid position is not well conserved in available vertebrate species. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.T1027M alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, 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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.059

.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.59

T;T;T

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.098

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.97

L;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.7

N;N;.

REVEL

Benign

0.19

Sift

Uncertain

0.0010

D;D;.

Sift4G

Benign

0.098

T;T;T

Polyphen

0.0090

B;B;.

Vest4

0.15

MutPred

0.23

Gain of catalytic residue at T1027 (P = 0);Gain of catalytic residue at T1027 (P = 0);.;

MVP

0.14

MPC

0.26

ClinPred

0.058

GERP RS

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.041

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over