NM_022489.4:c.37G>T

Variant names:

• chr14-104701402-G-T
• rs201383094
• NM_022489.4:c.37G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022489.4(INF2):​c.37G>T​(p.Ala13Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.50
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease dominant intermediate E

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• focal segmental glomerulosclerosis 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32331258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INF2	NM_022489.4	c.37G>T	p.Ala13Ser	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.37G>T	p.Ala13Ser	missense_variant	Exon 2 of 23	5	NM_022489.4	ENSP00000376410.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441078 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 714884

African (AFR) AF: 0.00 AC: 0 AN: 33056

American (AMR) AF: 0.00 AC: 0 AN: 42874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 38642

South Asian (SAS) AF: 0.00 AC: 0 AN: 83354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101566

Other (OTH) AF: 0.00 AC: 0 AN: 59496

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jun 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 13 of the INF2 protein (p.Ala13Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with INF2-related conditions. 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 not expected to disrupt INF2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	.;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.4	L;L;L
PhyloP100		6.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.034	D;T;D
Polyphen		1.0	D;.;D
Vest4		0.25
MutPred		0.54		Gain of phosphorylation at A13 (P = 0.0302);Gain of phosphorylation at A13 (P = 0.0302);Gain of phosphorylation at A13 (P = 0.0302);
MVP		0.66
MPC		2.3
ClinPred		0.94	D
GERP RS		4.3
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.76
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs201383094; hg19: chr14-105167739;