rs368995122

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022489.4(INF2):c.3103G>A(p.Gly1035Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,593,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. G1035R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

INF2
NM_022489.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5O:1

Conservation

PhyloP100: -0.0520

Publications

0 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

INF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02851376).

BP6

Variant 14-104714265-G-A is Benign according to our data. Variant chr14-104714265-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 387417.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000177 (27/152212) while in subpopulation NFE AF = 0.000323 (22/68036). AF 95% confidence interval is 0.000218. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INF2	NM_022489.4 link	c.3103G>A	p.Gly1035Ser	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
INF2	ENST00000392634.9 link	c.3103G>A	p.Gly1035Ser	missense_variant	Exon 21 of 23	5	NM_022489.4	ENSP00000376410.4		Q27J81-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000161

AC:

AN:

217250

AF XY:

0.000144

show subpopulations

Gnomad AFR exome

AF:

0.000165

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000557

Gnomad NFE exome

AF:

0.000328

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000306

AC:

441

AN:

1441530

Hom.:

Cov.:

AF XY:

0.000275

AC XY:

197

AN XY:

715382

show subpopulations

African (AFR)

AF:

0.0000607

AC:

AN:

32946

American (AMR)

AF:

0.00

AC:

AN:

42846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25532

East Asian (EAS)

AF:

0.00

AC:

AN:

38658

South Asian (SAS)

AF:

0.0000120

AC:

AN:

82990

European-Finnish (FIN)

AF:

0.0000202

AC:

AN:

49482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000385

AC:

425

AN:

1103722

Other (OTH)

AF:

0.000201

AC:

AN:

59620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000177

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000222

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.000117

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Jan 12, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The INF2 c.3103G>A; p.Gly1035Ser variant (rs368995122), to our knowledge, is not reported in the medical literature nor has it been previously identified by our laboratory. It is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.03% in the non-Finnish European population (identified in 33 out of 110,380 chromosomes), and is classified as likely benign/unknown significance in ClinVar (Variant ID: 387417). The glycine at position 1035 is weakly conserved, considering 12 species, and computational analyses of the effects of the p.Gly1035Ser variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Gly1035Ser variant cannot be determined with certainty. -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

INF2: PM2, BP4 -

Sep 16, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1Other:1

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 01-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not specified

Benign:1

Jun 30, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: INF2 c.3103G>A (p.Gly1035Ser) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00016 in 217250 control chromosomes. The observed variant frequency is approximately 257.77 fold of the estimated maximal expected allele frequency for a pathogenic variant in INF2 causing Charcot-Marie-Tooth disease dominant intermediate E phenotype (6.3e-07). To our knowledge, no occurrence of c.3103G>A in individuals affected with Charcot-Marie-Tooth disease dominant intermediate E and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 387417). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases

Benign:1

Jun 16, 2021

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Focal segmental glomerulosclerosis 5

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.067

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.4

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.033

.;T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.54

T;T;T

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.029

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.14

N;N;.

PhyloP100

-0.052

PrimateAI

Benign

0.30

PROVEAN

Benign

0.62

N;N;.

REVEL

Benign

0.24

Sift

Benign

1.0

T;T;.

Sift4G

Benign

0.48

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.024

MVP

0.23

MPC

0.25

ClinPred

0.0043

GERP RS

-3.3

Varity_R

0.024

gMVP

0.10

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over