rs186075307

chr14-104714270-T-C

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.3108T>C(p.Leu1036=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,594,960 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (6 hom., cov: 34)
  • Exomes 𝑓: 0.0064 (36 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.32

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=-0.92).
• BP6: Variant 14-104714270-T-C is Benign according to our data. Variant chr14-104714270-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 261615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104714270-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00527 (802/152224) while in subpopulation NFE AF= 0.00797 (542/67992). AF 95% confidence interval is 0.00742. There are 6 homozygotes in gnomad4. There are 391 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 804 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.3108T>C	p.Leu1036=	synonymous_variant	21/23	ENST00000392634.9
INF2	NM_001031714.4	c.3108T>C	p.Leu1036=	synonymous_variant	21/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.3108T>C	p.Leu1036=	synonymous_variant	21/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 804 AN: 152106 Hom.: 6 Cov.: 34

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00797

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00484 AC: 1056 AN: 218116 Hom.: 4 AF XY: 0.00472 AC XY: 562 AN XY: 118998

Gnomad AFR exome AF: 0.000905

Gnomad AMR exome AF: 0.00441

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00193

Gnomad NFE exome AF: 0.00753

Gnomad OTH exome AF: 0.00646

GnomAD4 exome AF: 0.00643 AC: 9273 AN: 1442736 Hom.: 36 Cov.: 69 AF XY: 0.00623 AC XY: 4461 AN XY: 716110

Gnomad4 AFR exome AF: 0.00112

Gnomad4 AMR exome AF: 0.00509

Gnomad4 ASJ exome AF: 0.00653

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.000938

Gnomad4 FIN exome AF: 0.00247

Gnomad4 NFE exome AF: 0.00745

Gnomad4 OTH exome AF: 0.00647

GnomAD4 genome AF: 0.00527 AC: 802 AN: 152224 Hom.: 6 Cov.: 34 AF XY: 0.00525 AC XY: 391 AN XY: 74432

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00712

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00797

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00745 Hom.: 1

Bravo AF: 0.00591

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 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, 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:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	INF2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 21, 2018	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 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 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	-0.92
Cadd	Benign	0.48
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs186075307; hg19: chr14-105180607; COSMIC: COSV99384688; COSMIC: COSV99384688;