NM_022489.4:c.3412C>G

Variant names:

• chr14-104714574-C-G
• rs759925463
• NM_022489.4:c.3412C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022489.4(INF2):​c.3412C>G​(p.Leu1138Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,460,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L1138L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.27
• 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041444093).
• BP6: Variant 14-104714574-C-G is Benign according to our data. Variant chr14-104714574-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 472853.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000164 (24/1460348) while in subpopulation MID AF = 0.000347 (2/5768). AF 95% confidence interval is 0.000143. There are 0 homozygotes in GnomAdExome4. There are 17 alleles in the male GnomAdExome4 subpopulation. Median coverage is 37. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022489.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	NM_022489.4	MANE Select	c.3412C>G	p.Leu1138Val	missense	Exon 21 of 23	NP_071934.3	Q27J81-1
	INF2	NM_001426862.1		c.3412C>G	p.Leu1138Val	missense	Exon 21 of 23	NP_001413791.1
	INF2	NM_001426863.1		c.3412C>G	p.Leu1138Val	missense	Exon 21 of 23	NP_001413792.1	Q27J81-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INF2	ENST00000392634.9	TSL:5 MANE Select	c.3412C>G	p.Leu1138Val	missense	Exon 21 of 23	ENSP00000376410.4	Q27J81-1
	INF2	ENST00000617571.5	TSL:1	n.*261C>G		non_coding_transcript_exon	Exon 20 of 22	ENSP00000483829.2	A0A087X118
	INF2	ENST00000617571.5	TSL:1	n.*261C>G		3_prime_UTR	Exon 20 of 22	ENSP00000483829.2	A0A087X118

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000404 AC: 10 AN: 247806 AF XY: 0.0000444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1460348 Hom.: 0 Cov.: 37 AF XY: 0.0000234 AC XY: 17 AN XY: 726458

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52086

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111854

Other (OTH) AF: 0.0000331 AC: 2 AN: 60360

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000331 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.47
DANN	Benign	0.77
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.3
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.092
Sift	Benign	0.31	T
Sift4G	Benign	0.64	T
Polyphen		0.21	B
Vest4		0.057
MutPred		0.15		Gain of catalytic residue at V1140 (P = 0.0208)
MVP		0.30
MPC		0.25
ClinPred		0.044	T
GERP RS		-0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.054
Mutation Taster		=99/1	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: rs759925463; hg19: chr14-105180911;