rs79327775

chr14-104711668-C-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.2458C>T(p.Arg820Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,612,460 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R820Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.130

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=0.0071008205).
• BP6: Variant 14-104711668-C-T is Benign according to our data. Variant chr14-104711668-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104711668-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00231 (351/152272) while in subpopulation AFR AF= 0.00753 (313/41548). AF 95% confidence interval is 0.00685. There are 1 homozygotes in gnomad4. There are 157 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 351 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.2458C>T	p.Arg820Trp	missense_variant	16/23	ENST00000392634.9
INF2	NM_001031714.4	c.2458C>T	p.Arg820Trp	missense_variant	16/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.2458C>T	p.Arg820Trp	missense_variant	16/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152154 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000696 AC: 172 AN: 246970 Hom.: 0 AF XY: 0.000580 AC XY: 78 AN XY: 134570

Gnomad AFR exome AF: 0.00739

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000785

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000405 AC: 592 AN: 1460188 Hom.: 4 Cov.: 32 AF XY: 0.000425 AC XY: 309 AN XY: 726364

Gnomad4 AFR exome AF: 0.00747

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000928

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.00231 AC: 351 AN: 152272 Hom.: 1 Cov.: 33 AF XY: 0.00211 AC XY: 157 AN XY: 74450

Gnomad4 AFR AF: 0.00753

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000800 Hom.: 0

Bravo AF: 0.00234

ESP6500AA AF: 0.00567 AC: 23

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000903 AC: 109

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	INF2: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 09, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.062	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0071	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Benign	0.045
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.95	P;D;.
Vest4		0.19
MVP		0.11
MPC		0.26
ClinPred		0.034	T
GERP RS		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.28

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: rs79327775; hg19: chr14-105178005;