rs199526439

chr14-104709620-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022489.4(INF2):c.2053A>G(p.Ile685Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000246 in 1,612,126 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. I685T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (6 hom.)
• Consequence: INF2 NM_022489.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004806
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.701

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04631102).
• BP6: Variant 14-104709620-A-G is Benign according to our data. Variant chr14-104709620-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 312700.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000204 (31/152280) while in subpopulation SAS AF= 0.000415 (2/4822). AF 95% confidence interval is 0.00017. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.2053A>G	p.Ile685Val	missense_variant, splice_region_variant	12/23	ENST00000392634.9
INF2	NM_001031714.4	c.2053A>G	p.Ile685Val	missense_variant, splice_region_variant	12/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.2053A>G	p.Ile685Val	missense_variant, splice_region_variant	12/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000201 AC: 50 AN: 248200 Hom.: 0 AF XY: 0.000200 AC XY: 27 AN XY: 135080

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000259

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.000251 AC: 366 AN: 1459846 Hom.: 6 Cov.: 32 AF XY: 0.000278 AC XY: 202 AN XY: 726260

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000173

Gnomad4 OTH exome AF: 0.000680

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74466

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000196

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000166 AC: 20

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2020	This variant is associated with the following publications: (PMID: 23349334, 32451589, 32444357) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 14, 2019	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 685 of the INF2 protein (p.Ile685Val). This variant is present in population databases (rs199526439, gnomAD 0.03%). This missense change has been observed in individual(s) with steroid-resistant nephrotic syndrome (PMID: 23349334, 23515051). ClinVar contains an entry for this variant (Variation ID: 312700). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	9.9
Dann	Benign	0.51
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;L;.
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.52	N;N;N
REVEL	Benign	0.025
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.047	B;B;.
Vest4		0.13
MVP		0.19
MPC		0.21
ClinPred		0.0099	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0080
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: rs199526439; hg19: chr14-105175957; COSMIC: COSV53033944; COSMIC: COSV53033944;