chr14-104701748-T-C

Variant names:

• chr14-104701748-T-C
• rs387907037
• NM_022489.4:c.383T>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_022489.4(INF2):​c.383T>C​(p.Leu128Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.14

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 14-104701748-T-C is Pathogenic according to our data. Variant chr14-104701748-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 30867.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.383T>C	p.Leu128Pro	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.383T>C	p.Leu128Pro	missense_variant	Exon 2 of 23	5	NM_022489.4	ENSP00000376410.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1356128 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 664024

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 128 of the INF2 protein (p.Leu128Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis (PMID: 22187985, 22961558). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30867). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

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

Dec 22, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Jun 17, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L128P variant (also known as c.383T>C), located in coding exon 1 of the INF2 gene, results from a T to C substitution at nucleotide position 383. The leucine at codon 128 is replaced by proline, an amino acid with similar properties. This alteration is located in the diaphanous inhibitory domain (DID), where pathogenic alterations are localized between nucleotide positions 300 to 500 in patients with both Charcot-Marie-Tooth disease, intermediate E (CMTDIE) and focal segmental glomerulosclerosis 5 (FSGS) (Boyer O et al. N. Engl. J. Med., 2011 Dec;365:2377-88). This variant has been found in multiple individuals with CMT and FSGS and was reported as de novo in one individual (Boyer O et al. N. Engl. J. Med., 2011 Dec;365:2377-88; Rodriguez PQ et al. Pediatr. Nephrol., 2013 Feb;28:339-43). The variant has also been reported in one individual with an unspecified inherited neuropathy phenotype (Laššuthová P et al. Orphanet J Rare Dis, 2016 08;11:118). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Dec 10, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on actin stress response (PMID: 32444357); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24487800, 27549087, 25439738, 22961558, 32033020, 36637069, Bittmann2023[Case Report], 22965130, 39623687, 22187985, 38916773, 39609740, 32444357) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	2.9	M;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.93
MutPred		0.68		Gain of catalytic residue at R126 (P = 0.0075);Gain of catalytic residue at R126 (P = 0.0075);Gain of catalytic residue at R126 (P = 0.0075);
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.98
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: rs387907037; hg19: chr14-105168085;