rs59751492

chr14-104711090-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022489.4(INF2):c.2322C>T(p.Thr774=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00503 in 1,598,020 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (120 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (116 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -9.08

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 14-104711090-C-T is Benign according to our data. Variant chr14-104711090-C-T is described in ClinVar as [Benign]. Clinvar id is 261607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104711090-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-9.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.2322C>T	p.Thr774=	synonymous_variant	15/23	ENST00000392634.9
INF2	NM_001031714.4	c.2322C>T	p.Thr774=	synonymous_variant	15/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.2322C>T	p.Thr774=	synonymous_variant	15/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3379 AN: 152168 Hom.: 121 Cov.: 33

Gnomad AFR AF: 0.0742

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00662

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.00644 AC: 1408 AN: 218664 Hom.: 31 AF XY: 0.00539 AC XY: 646 AN XY: 119786

Gnomad AFR exome AF: 0.0737

Gnomad AMR exome AF: 0.00412

Gnomad ASJ exome AF: 0.00953

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00628

Gnomad FIN exome AF: 0.000105

Gnomad NFE exome AF: 0.000882

Gnomad OTH exome AF: 0.00512

GnomAD4 exome AF: 0.00322 AC: 4651 AN: 1445734 Hom.: 116 Cov.: 34 AF XY: 0.00309 AC XY: 2219 AN XY: 718332

Gnomad4 AFR exome AF: 0.0756

Gnomad4 AMR exome AF: 0.00486

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0000789

Gnomad4 SAS exome AF: 0.00591

Gnomad4 FIN exome AF: 0.0000590

Gnomad4 NFE exome AF: 0.000605

Gnomad4 OTH exome AF: 0.00793

GnomAD4 genome AF: 0.0222 AC: 3383 AN: 152286 Hom.: 120 Cov.: 33 AF XY: 0.0212 AC XY: 1582 AN XY: 74464

Gnomad4 AFR AF: 0.0741

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0111 Hom.: 16

Bravo AF: 0.0253

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

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

- -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2018

- -

Focal segmental glomerulosclerosis 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.036
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs59751492; hg19: chr14-105177427;