rs918089359

Positions:

• chr14-104701583-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_022489.4(INF2):​c.218G>T​(p.Gly73Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G73C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.75

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]

INF2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-104701582-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 14-104701583-G-T is Pathogenic according to our data. Variant chr14-104701583-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 472842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INF2	NM_022489.4	c.218G>T	p.Gly73Val	missense_variant	2/23	ENST00000392634.9	NP_071934.3
INF2	NM_001031714.4	c.218G>T	p.Gly73Val	missense_variant	2/22		NP_001026884.3
INF2	NM_032714.3	c.218G>T	p.Gly73Val	missense_variant	2/5		NP_116103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9	c.218G>T	p.Gly73Val	missense_variant	2/23	5	NM_022489.4	ENSP00000376410.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455218 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 723904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 07, 2020

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of INF2-related conditions (PMID: 31937884, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 472842). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 73 of the INF2 protein (p.Gly73Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 11, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31937884, 37491439, 22965130, Fujii2023[casereport], 23014460, 31096240) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.91
MutPred		0.71		Gain of catalytic residue at G73 (P = 0.0537);Gain of catalytic residue at G73 (P = 0.0537);Gain of catalytic residue at G73 (P = 0.0537);
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		1.0

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: rs918089359; hg19: chr14-105167920; COSMIC: COSV99043368;