rs760488958

Positions:

• chr14-104714242-C-G
• chr14-104714242-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022489.4(INF2):​c.3080C>G​(p.Thr1027Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.634

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12917769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INF2	NM_022489.4	c.3080C>G	p.Thr1027Arg	missense_variant	21/23	ENST00000392634.9	NP_071934.3
INF2	NM_001031714.4	c.3080C>G	p.Thr1027Arg	missense_variant	21/22		NP_001026884.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9	c.3080C>G	p.Thr1027Arg	missense_variant	21/23	5	NM_022489.4	ENSP00000376410	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 34

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 1027 of the INF2 protein (p.Thr1027Arg). 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	0.071
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.75
DEOGEN2	Benign	0.048	.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.97	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;N;.
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;D;.
Sift4G	Benign	0.61	T;T;T
Polyphen		0.31	B;B;.
Vest4		0.14
MutPred		0.25		Gain of catalytic residue at T1027 (P = 0.0042);Gain of catalytic residue at T1027 (P = 0.0042);.;
MVP		0.21
MPC		0.28
ClinPred		0.40	T
GERP RS		0.35
Varity_R		0.13
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760488958; hg19: chr14-105180579;