rs142678449

Positions:

chr14-104712847-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_022489.4(INF2):c.2630G>A(p.Arg877Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,611,314 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 13 hom., cov: 35)

Exomes 𝑓: 0.010 ( 115 hom. )

Consequence

INF2
NM_022489.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.540

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 -16 ACMG points.

BP6

Variant 14-104712847-G-A is Benign according to our data. Variant chr14-104712847-G-A is described in ClinVar as [Benign]. Clinvar id is 261610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104712847-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00787 (1199/152334) while in subpopulation NFE AF= 0.0106 (723/68020). AF 95% confidence interval is 0.00999. There are 13 homozygotes in gnomad4. There are 560 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INF2	NM_022489.4 linkuse as main transcript	c.2630G>A	p.Arg877Gln	missense_variant	18/23	ENST00000392634.9	NP_071934.3
INF2	NM_001031714.4 linkuse as main transcript	c.2630G>A	p.Arg877Gln	missense_variant	18/22		NP_001026884.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9 linkuse as main transcript	c.2630G>A	p.Arg877Gln	missense_variant	18/23	5	NM_022489.4	ENSP00000376410	P4	Q27J81-1

Frequencies

GnomAD3 genomes

AF:

0.00786

AC:

1196

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00818

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00972

Gnomad FIN

AF:

0.00546

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.0138

GnomAD3 exomes

AF:

0.0101

AC:

2491

AN:

246068

Hom.:

AF XY:

0.0107

AC XY:

1437

AN XY:

134364

show subpopulations

Gnomad AFR exome

AF:

0.00244

Gnomad AMR exome

AF:

0.00680

Gnomad ASJ exome

AF:

0.0316

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0129

Gnomad FIN exome

AF:

0.00792

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0105

AC:

15310

AN:

1458980

Hom.:

115

Cov.:

AF XY:

0.0107

AC XY:

7747

AN XY:

725566

show subpopulations

Gnomad4 AFR exome

AF:

0.00233

Gnomad4 AMR exome

AF:

0.00687

Gnomad4 ASJ exome

AF:

0.0319

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0121

Gnomad4 FIN exome

AF:

0.00854

Gnomad4 NFE exome

AF:

0.0106

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.00787

AC:

1199

AN:

152334

Hom.:

Cov.:

AF XY:

0.00752

AC XY:

560

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.00810

Gnomad4 ASJ

AF:

0.0285

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00952

Gnomad4 FIN

AF:

0.00546

Gnomad4 NFE

AF:

0.0106

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.00788

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00149

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00957

AC:

1154

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0133

EpiControl

AF:

0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 24, 2022	- -

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	INF2: PP3, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Focal segmental glomerulosclerosis 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.039

.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0074

LIST_S2

Benign

0.72

T;T;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.56

N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.3

N;N;.

REVEL

Benign

0.069

Sift

Benign

0.44

T;T;.

Sift4G

Benign

0.20

T;T;T

Polyphen

0.093

B;B;.

Vest4

0.063

MPC

0.28

ClinPred

0.0080

GERP RS

-4.1

Varity_R

0.033

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.66

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.66

Position offset: 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