14-104714228-T-C

Variant names:

• chr14-104714228-T-C
• rs4983535
• NM_022489.4:c.3066T>C

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.3066T>C​(p.Asp1022Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.772 in 1,556,818 control chromosomes in the GnomAD database, including 465,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48839 hom., cov: 34)
  • Exomes 𝑓: 0.77 (416226 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0870

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=-0.94).
• BP6: Variant 14-104714228-T-C is Benign according to our data. Variant chr14-104714228-T-C is described in ClinVar as [Benign]. Clinvar id is 261613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104714228-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.087 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INF2	NM_022489.4	c.3066T>C	p.Asp1022Asp	synonymous_variant	Exon 21 of 23	ENST00000392634.9	NP_071934.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9	c.3066T>C	p.Asp1022Asp	synonymous_variant	Exon 21 of 23	5	NM_022489.4	ENSP00000376410.4

Frequencies

GnomAD3 genomes AF: 0.799 AC: 121428 AN: 152000 Hom.: 48799 Cov.: 34

Gnomad AFR AF: 0.867

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.833

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.744

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.820

GnomAD3 exomes AF: 0.787 AC: 142897 AN: 181548 Hom.: 56711 AF XY: 0.778 AC XY: 76100 AN XY: 97840

Gnomad AFR exome AF: 0.865

Gnomad AMR exome AF: 0.850

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.934

Gnomad SAS exome AF: 0.730

Gnomad FIN exome AF: 0.722

Gnomad NFE exome AF: 0.752

Gnomad OTH exome AF: 0.776

GnomAD4 exome AF: 0.769 AC: 1079694 AN: 1404700 Hom.: 416226 Cov.: 59 AF XY: 0.766 AC XY: 531282 AN XY: 693164

Gnomad4 AFR exome AF: 0.875

Gnomad4 AMR exome AF: 0.848

Gnomad4 ASJ exome AF: 0.800

Gnomad4 EAS exome AF: 0.922

Gnomad4 SAS exome AF: 0.735

Gnomad4 FIN exome AF: 0.735

Gnomad4 NFE exome AF: 0.760

Gnomad4 OTH exome AF: 0.780

GnomAD4 genome AF: 0.799 AC: 121523 AN: 152118 Hom.: 48839 Cov.: 34 AF XY: 0.799 AC XY: 59386 AN XY: 74342

Gnomad4 AFR AF: 0.867

Gnomad4 AMR AF: 0.833

Gnomad4 ASJ AF: 0.794

Gnomad4 EAS AF: 0.930

Gnomad4 SAS AF: 0.734

Gnomad4 FIN AF: 0.744

Gnomad4 NFE AF: 0.753

Gnomad4 OTH AF: 0.819

Alfa AF: 0.746 Hom.: 7189

Bravo AF: 0.813

Asia WGS AF: 0.852 AC: 2961 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 98% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 91. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 21, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 25, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease dominant intermediate E Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis 5 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.94
CADD	Benign	1.1
DANN	Benign	0.33

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: rs4983535; hg19: chr14-105180565; COSMIC: COSV53036802; COSMIC: COSV53036802;