rs200369827

chr14-104714296-G-Achr14-104714296-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022489.4(INF2):c.3134G>A(p.Arg1045Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,591,924 control chromosomes in the GnomAD database, including 7 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1045W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (5 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.22

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051357746).
• BP6: Variant 14-104714296-G-A is Benign according to our data. Variant chr14-104714296-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 312706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00129 (197/152296) while in subpopulation NFE AF= 0.00182 (124/68016). AF 95% confidence interval is 0.00156. There are 2 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 192 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.3134G>A	p.Arg1045Gln	missense_variant	21/23	ENST00000392634.9
INF2	NM_001031714.4	c.3134G>A	p.Arg1045Gln	missense_variant	21/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.3134G>A	p.Arg1045Gln	missense_variant	21/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152178 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00101 AC: 212 AN: 210028 Hom.: 0 AF XY: 0.000987 AC XY: 113 AN XY: 114492

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.000357

Gnomad ASJ exome AF: 0.000980

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000113

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.000561

GnomAD4 exome AF: 0.00122 AC: 1757 AN: 1439628 Hom.: 5 Cov.: 70 AF XY: 0.00123 AC XY: 877 AN XY: 714462

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.000310

Gnomad4 ASJ exome AF: 0.000624

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000723

Gnomad4 FIN exome AF: 0.000400

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.000973

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152296 Hom.: 2 Cov.: 34 AF XY: 0.00106 AC XY: 79 AN XY: 74468

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.00128

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00179 AC: 7

ESP6500EA AF: 0.00146 AC: 12

ExAC AF: 0.00124 AC: 148

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	INF2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2021	This variant is associated with the following publications: (PMID: 26378787) -

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2019

This alteration is classified as likely 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

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. -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

INF2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.0040
Dann	Benign	0.42
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.0051	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.63	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.32	N;N;.
REVEL	Benign	0.13
Sift	Benign	0.60	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.010	B;B;.
Vest4		0.054
MVP		0.33
MPC		0.28
ClinPred		0.0011	T
GERP RS		-7.4
Varity_R		0.015
gMVP		0.064

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs200369827; hg19: chr14-105180633;