14-104714566-C-A

Variant names:

• chr14-104714566-C-A
• rs3803311
• NM_022489.4:c.3404C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022489.4(INF2):​c.3404C>A​(p.Thr1135Lys) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1135M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.107
• Publications: 9 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055829138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INF2	NM_022489.4	c.3404C>A	p.Thr1135Lys	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.3404C>A	p.Thr1135Lys	missense_variant	Exon 21 of 23	5	NM_022489.4	ENSP00000376410.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 11

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.2
DANN	Benign	0.42
DEOGEN2	Benign	0.058	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.38	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.55	N;N;.
PhyloP100		-0.11
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N;N;.
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;.
Sift4G	Benign	0.91	T;T;T
Polyphen		0.23	B;B;.
Vest4		0.049
MutPred		0.18		Gain of ubiquitination at T1135 (P = 0.0014);Gain of ubiquitination at T1135 (P = 0.0014);.;
MVP		0.21
MPC		0.30
ClinPred		0.11	T
GERP RS		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.16
Mutation Taster		=100/0	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: rs3803311; hg19: chr14-105180903;