14-104701470-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.105C>T(p.Pro35=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.978 in 1,600,582 control chromosomes in the GnomAD database, including 765,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (73251 hom., cov: 36)
  • Exomes 𝑓: 0.98 (692060 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.64

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=-0.63).
• BP6: Variant 14-104701470-C-T is Benign according to our data. Variant chr14-104701470-C-T is described in ClinVar as [Benign]. Clinvar id is 261603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104701470-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.105C>T	p.Pro35=	synonymous_variant	2/23	ENST00000392634.9
INF2	NM_001031714.4	c.105C>T	p.Pro35=	synonymous_variant	2/22
INF2	NM_032714.3	c.105C>T	p.Pro35=	synonymous_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.105C>T	p.Pro35=	synonymous_variant	2/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.980 AC: 149265 AN: 152248 Hom.: 73193 Cov.: 36

Gnomad AFR AF: 0.995

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.975

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.989

Gnomad FIN AF: 0.963

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.975

Gnomad OTH AF: 0.970

GnomAD3 exomes AF: 0.978 AC: 219351 AN: 224292 Hom.: 107294 AF XY: 0.978 AC XY: 120087 AN XY: 122848

Gnomad AFR exome AF: 0.996

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.957

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.987

Gnomad FIN exome AF: 0.962

Gnomad NFE exome AF: 0.974

Gnomad OTH exome AF: 0.968

GnomAD4 exome AF: 0.978 AC: 1415694 AN: 1448216 Hom.: 692060 Cov.: 82 AF XY: 0.978 AC XY: 703233 AN XY: 719300

Gnomad4 AFR exome AF: 0.996

Gnomad4 AMR exome AF: 0.981

Gnomad4 ASJ exome AF: 0.954

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.988

Gnomad4 FIN exome AF: 0.962

Gnomad4 NFE exome AF: 0.977

Gnomad4 OTH exome AF: 0.977

GnomAD4 genome AF: 0.980 AC: 149382 AN: 152366 Hom.: 73251 Cov.: 36 AF XY: 0.980 AC XY: 73034 AN XY: 74510

Gnomad4 AFR AF: 0.995

Gnomad4 AMR AF: 0.975

Gnomad4 ASJ AF: 0.950

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.989

Gnomad4 FIN AF: 0.963

Gnomad4 NFE AF: 0.975

Gnomad4 OTH AF: 0.971

Alfa AF: 0.974 Hom.: 113328

Bravo AF: 0.982

Asia WGS AF: 0.997 AC: 3468 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 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, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Focal segmental glomerulosclerosis 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	3.6
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4983530; hg19: chr14-105167807;