chr14-104714221-C-A

Variant names:

• chr14-104714221-C-A
• rs368372551
• NM_022489.4:c.3059C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022489.4(INF2):​c.3059C>A​(p.Ala1020Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A1020V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.18
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072129965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INF2	NM_022489.4	c.3059C>A	p.Ala1020Glu	missense_variant	Exon 21 of 23	ENST00000392634.9	NP_071934.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9	c.3059C>A	p.Ala1020Glu	missense_variant	Exon 21 of 23	5	NM_022489.4	ENSP00000376410.4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395624 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 687510

African (AFR) AF: 0.00 AC: 0 AN: 32096

American (AMR) AF: 0.00 AC: 0 AN: 39230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22876

East Asian (EAS) AF: 0.00 AC: 0 AN: 37308

South Asian (SAS) AF: 0.00 AC: 0 AN: 75312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1080866

Other (OTH) AF: 0.00 AC: 0 AN: 57832

GnomAD4 genome Cov.: 35

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

Feb 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with INF2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces alanine with glutamic acid at codon 1020 of the INF2 protein (p.Ala1020Glu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.8
DANN	Benign	0.69
DEOGEN2	Benign	0.030	.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.47	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.55	N;N;.
PhyloP100		-3.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.81	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.031	D;D;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.36	B;B;.
Vest4		0.12
MutPred		0.17		Gain of catalytic residue at G1021 (P = 8e-04);Gain of catalytic residue at G1021 (P = 8e-04);.;
MVP		0.24
MPC		0.29
ClinPred		0.091	T
GERP RS		-5.6
Varity_R		0.13
gMVP		0.30
Mutation Taster		=97/3	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: rs368372551; hg19: chr14-105180558;