rs62638758

chr14-104701407-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022489.4(INF2):c.42G>A(p.Leu14=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,594,304 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (32 hom., cov: 33)
  • Exomes 𝑓: 0.016 (284 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.932

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=-0.58).
• BP6: Variant 14-104701407-G-A is Benign according to our data. Variant chr14-104701407-G-A is described in ClinVar as [Benign]. Clinvar id is 261625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104701407-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.932 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0132 (2009/152372) while in subpopulation SAS AF= 0.0447 (216/4828). AF 95% confidence interval is 0.0399. There are 32 homozygotes in gnomad4. There are 1099 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2014 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.42G>A	p.Leu14=	synonymous_variant	2/23	ENST00000392634.9
INF2	NM_001031714.4	c.42G>A	p.Leu14=	synonymous_variant	2/22
INF2	NM_032714.3	c.42G>A	p.Leu14=	synonymous_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.42G>A	p.Leu14=	synonymous_variant	2/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2014 AN: 152254 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.0453

Gnomad FIN AF: 0.0425

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0185 AC: 3979 AN: 214528 Hom.: 75 AF XY: 0.0195 AC XY: 2288 AN XY: 117212

Gnomad AFR exome AF: 0.00248

Gnomad AMR exome AF: 0.00700

Gnomad ASJ exome AF: 0.00922

Gnomad EAS exome AF: 0.0186

Gnomad SAS exome AF: 0.0395

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0158 AC: 22802 AN: 1441932 Hom.: 284 Cov.: 31 AF XY: 0.0164 AC XY: 11734 AN XY: 715386

Gnomad4 AFR exome AF: 0.00187

Gnomad4 AMR exome AF: 0.00731

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.0379

Gnomad4 FIN exome AF: 0.0400

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.0155

GnomAD4 genome AF: 0.0132 AC: 2009 AN: 152372 Hom.: 32 Cov.: 33 AF XY: 0.0147 AC XY: 1099 AN XY: 74514

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.00908

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.0172

Gnomad4 SAS AF: 0.0447

Gnomad4 FIN AF: 0.0425

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0126 Hom.: 9

Bravo AF: 0.00973

Asia WGS AF: 0.0420 AC: 145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 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. -

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 27, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -

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

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	8.7
Dann	Benign	0.94

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: rs62638758; hg19: chr14-105167744;