rs918089359

Variant names:

• chr14-104701583-G-A
• NM_022489.4:c.218G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-104701583-G-A
• chr14-104701583-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_022489.4(INF2):​c.218G>A​(p.Gly73Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: 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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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, 0.922
• PP5: Variant 14-104701583-G-A is Pathogenic according to our data. Variant chr14-104701583-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1999164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INF2	NM_022489.4	c.218G>A	p.Gly73Asp	missense_variant	Exon 2 of 23	ENST00000392634.9	NP_071934.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9	c.218G>A	p.Gly73Asp	missense_variant	Exon 2 of 23	5	NM_022489.4	ENSP00000376410.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: 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

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 73 of the INF2 protein (p.Gly73Asp). This variant is not present in population databases (gnomAD no frequency). This variant disrupts the p.Gly73 amino acid residue in INF2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31937884; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This missense change has been observed in individual(s) with clinical features of INF2-related conditions (Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt INF2 protein function. -

Charcot-Marie-Tooth disease dominant intermediate E Pathogenic:1

Mar 25, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
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	0.94	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.91
MutPred		0.67		Gain of catalytic residue at E70 (P = 0.0274);Gain of catalytic residue at E70 (P = 0.0274);Gain of catalytic residue at E70 (P = 0.0274);
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		0.97
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-105167920;