rs73347508

chr14-104713007-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022489.4(INF2):c.2775+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,611,780 control chromosomes in the GnomAD database, including 1,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (978 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (878 hom.)
• Consequence: INF2 NM_022489.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.47

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-104713007-C-T is Benign according to our data. Variant chr14-104713007-C-T is described in ClinVar as [Benign]. Clinvar id is 261612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104713007-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.2775+15C>T		intron_variant		ENST00000392634.9
INF2	NM_001031714.4	c.2775+15C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.2775+15C>T		intron_variant		5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.0621 AC: 9457 AN: 152164 Hom.: 977 Cov.: 33

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.0454

GnomAD3 exomes AF: 0.0163 AC: 4021 AN: 246684 Hom.: 369 AF XY: 0.0127 AC XY: 1708 AN XY: 134608

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00180

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000981

Gnomad OTH exome AF: 0.00882

GnomAD4 exome AF: 0.00673 AC: 9822 AN: 1459498 Hom.: 878 Cov.: 36 AF XY: 0.00589 AC XY: 4280 AN XY: 726064

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00176

Gnomad4 FIN exome AF: 0.0000385

Gnomad4 NFE exome AF: 0.000610

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0622 AC: 9465 AN: 152282 Hom.: 978 Cov.: 33 AF XY: 0.0600 AC XY: 4472 AN XY: 74474

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.0232

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0328 Hom.: 78

Bravo AF: 0.0703

Asia WGS AF: 0.0120 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 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	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

Jan 31, 2024

- -

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	-0.90
Cadd	Benign	2.6
Dann	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs73347508; hg19: chr14-105179344;