rs142678449

chr14-104712847-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_022489.4(INF2):c.2630G>A(p.Arg877Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,611,314 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R877W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0079 (13 hom., cov: 35)
  • Exomes 𝑓: 0.010 (115 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.540

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 -16 ACMG points.

• BP6: Variant 14-104712847-G-A is Benign according to our data. Variant chr14-104712847-G-A is described in ClinVar as [Benign]. Clinvar id is 261610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-104712847-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00787 (1199/152334) while in subpopulation NFE AF= 0.0106 (723/68020). AF 95% confidence interval is 0.00999. There are 13 homozygotes in gnomad4. There are 560 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd at 1196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.2630G>A	p.Arg877Gln	missense_variant	18/23	ENST00000392634.9
INF2	NM_001031714.4	c.2630G>A	p.Arg877Gln	missense_variant	18/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.2630G>A	p.Arg877Gln	missense_variant	18/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.00786 AC: 1196 AN: 152216 Hom.: 12 Cov.: 35

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00972

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0101 AC: 2491 AN: 246068 Hom.: 19 AF XY: 0.0107 AC XY: 1437 AN XY: 134364

Gnomad AFR exome AF: 0.00244

Gnomad AMR exome AF: 0.00680

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.00792

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0105 AC: 15310 AN: 1458980 Hom.: 115 Cov.: 32 AF XY: 0.0107 AC XY: 7747 AN XY: 725566

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.00687

Gnomad4 ASJ exome AF: 0.0319

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.00854

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.00787 AC: 1199 AN: 152334 Hom.: 13 Cov.: 35 AF XY: 0.00752 AC XY: 560 AN XY: 74498

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.00810

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00952

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0115 Hom.: 14

Bravo AF: 0.00788

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00149 AC: 6

ESP6500EA AF: 0.0107 AC: 89

ExAC AF: 0.00957 AC: 1154

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0133

EpiControl AF: 0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	GeneDx	Jul 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 24, 2022	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	INF2: PP3, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	12
Dann	Benign	0.95
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0074	N
LIST_S2	Benign	0.72	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.56	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Benign	0.069
Sift	Benign	0.44	T;T;.
Sift4G	Benign	0.20	T;T;T
Polyphen		0.093	B;B;.
Vest4		0.063
MPC		0.28
ClinPred		0.0080	T
GERP RS		-4.1
Varity_R		0.033
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.66		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs142678449; hg19: chr14-105179184; COSMIC: COSV99043378; COSMIC: COSV99043378;