dbSNP rs368995122: INF2:p.Gly1035Ser (chr14-104714265-G-A) – ACMG Classification: Benign (-13 pts)

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:6O: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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022489.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INF2	NM_022489.4	MANE Select	c.3103G>A	p.Gly1035Ser	missense	Exon 21 of 23	NP_071934.3	Q27J81-1
INF2	NM_001426862.1		c.3103G>A	p.Gly1035Ser	missense	Exon 21 of 23	NP_001413791.1
INF2	NM_001426863.1		c.3103G>A	p.Gly1035Ser	missense	Exon 21 of 23	NP_001413792.1	Q27J81-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INF2	ENST00000392634.9	TSL:5 MANE Select	c.3103G>A	p.Gly1035Ser	missense	Exon 21 of 23	ENSP00000376410.4	Q27J81-1
INF2	ENST00000617571.5	TSL:1	n.3099G>A		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2	A0A087X118
INF2	ENST00000675207.1		c.3199G>A	p.Gly1067Ser	missense	Exon 21 of 23	ENSP00000502644.1	A0A6Q8PHA2

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Focal segmental glomerulosclerosis 5 (1)

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E (2)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.54

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.14

PhyloP100

-0.052

PrimateAI

Benign

0.30

PROVEAN

Benign

0.62

REVEL

Benign

0.24

Sift

Benign

1.0

Sift4G

Benign

0.48

Polyphen

0.0010

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over