14-104714315-C-T

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.3153C>T(p.Asp1051=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,589,492 control chromosomes in the GnomAD database, including 296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (30 hom., cov: 34)
  • Exomes 𝑓: 0.015 (266 hom.)
• Consequence: INF2 NM_022489.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.34

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=-0.76).
• BP6: Variant 14-104714315-C-T is Benign according to our data. Variant chr14-104714315-C-T is described in ClinVar as [Benign]. Clinvar id is 261616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104714315-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0131 (1993/152122) while in subpopulation SAS AF= 0.0453 (218/4810). AF 95% confidence interval is 0.0404. There are 30 homozygotes in gnomad4. There are 1098 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 1998 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.3153C>T	p.Asp1051=	synonymous_variant	21/23	ENST00000392634.9
INF2	NM_001031714.4	c.3153C>T	p.Asp1051=	synonymous_variant	21/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.3153C>T	p.Asp1051=	synonymous_variant	21/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1998 AN: 152004 Hom.: 30 Cov.: 34

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0155

Gnomad SAS AF: 0.0459

Gnomad FIN AF: 0.0426

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0193 AC: 3969 AN: 205650 Hom.: 67 AF XY: 0.0203 AC XY: 2275 AN XY: 111870

Gnomad AFR exome AF: 0.00231

Gnomad AMR exome AF: 0.00731

Gnomad ASJ exome AF: 0.00916

Gnomad EAS exome AF: 0.0204

Gnomad SAS exome AF: 0.0413

Gnomad FIN exome AF: 0.0387

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0154 AC: 22092 AN: 1437370 Hom.: 266 Cov.: 70 AF XY: 0.0160 AC XY: 11407 AN XY: 713118

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00742

Gnomad4 ASJ exome AF: 0.00991

Gnomad4 EAS exome AF: 0.0179

Gnomad4 SAS exome AF: 0.0393

Gnomad4 FIN exome AF: 0.0404

Gnomad4 NFE exome AF: 0.0132

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0131 AC: 1993 AN: 152122 Hom.: 30 Cov.: 34 AF XY: 0.0148 AC XY: 1098 AN XY: 74380

Gnomad4 AFR AF: 0.00239

Gnomad4 AMR AF: 0.00994

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.0154

Gnomad4 SAS AF: 0.0453

Gnomad4 FIN AF: 0.0426

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0121 Hom.: 6

Bravo AF: 0.00954

Asia WGS AF: 0.0420 AC: 146 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-0.76
Cadd	Benign	0.14
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs117457867; hg19: chr14-105180652;