rs10133301

chr14-104712857-T-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.2640T>C(p.Asp880=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.851 in 1,612,146 control chromosomes in the GnomAD database, including 585,888 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59656 hom., cov: 35)
  • Exomes 𝑓: 0.85 (526232 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.25

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=-0.93).
• BP6: Variant 14-104712857-T-C is Benign according to our data. Variant chr14-104712857-T-C is described in ClinVar as [Benign]. Clinvar id is 261611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104712857-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.2640T>C	p.Asp880=	synonymous_variant	18/23	ENST00000392634.9
INF2	NM_001031714.4	c.2640T>C	p.Asp880=	synonymous_variant	18/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.2640T>C	p.Asp880=	synonymous_variant	18/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.882 AC: 134253 AN: 152184 Hom.: 59598 Cov.: 35

Gnomad AFR AF: 0.971

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.901

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.816

Gnomad FIN AF: 0.789

Gnomad MID AF: 0.911

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.902

GnomAD3 exomes AF: 0.861 AC: 212235 AN: 246426 Hom.: 91725 AF XY: 0.855 AC XY: 114975 AN XY: 134476

Gnomad AFR exome AF: 0.975

Gnomad AMR exome AF: 0.901

Gnomad ASJ exome AF: 0.905

Gnomad EAS exome AF: 0.948

Gnomad SAS exome AF: 0.819

Gnomad FIN exome AF: 0.785

Gnomad NFE exome AF: 0.841

Gnomad OTH exome AF: 0.871

GnomAD4 exome AF: 0.848 AC: 1238245 AN: 1459844 Hom.: 526232 Cov.: 72 AF XY: 0.847 AC XY: 615049 AN XY: 726154

Gnomad4 AFR exome AF: 0.977

Gnomad4 AMR exome AF: 0.902

Gnomad4 ASJ exome AF: 0.904

Gnomad4 EAS exome AF: 0.939

Gnomad4 SAS exome AF: 0.819

Gnomad4 FIN exome AF: 0.787

Gnomad4 NFE exome AF: 0.842

Gnomad4 OTH exome AF: 0.865

GnomAD4 genome AF: 0.882 AC: 134368 AN: 152302 Hom.: 59656 Cov.: 35 AF XY: 0.880 AC XY: 65550 AN XY: 74474

Gnomad4 AFR AF: 0.972

Gnomad4 AMR AF: 0.901

Gnomad4 ASJ AF: 0.903

Gnomad4 EAS AF: 0.942

Gnomad4 SAS AF: 0.814

Gnomad4 FIN AF: 0.789

Gnomad4 NFE AF: 0.838

Gnomad4 OTH AF: 0.903

Alfa AF: 0.855 Hom.: 59253

Bravo AF: 0.897

Asia WGS AF: 0.912 AC: 3168 AN: 3476

EpiCase AF: 0.843

EpiControl AF: 0.855

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2015	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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.23
Dann	Benign	0.23

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: rs10133301; hg19: chr14-105179194; COSMIC: COSV53030370; COSMIC: COSV53030370;