14-104703445-G-C

Position:

• chr14-104703445-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_022489.4(INF2):​c.658G>C​(p.Glu220Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. E220K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_022489.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-104703445-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.658G>C	p.Glu220Gln	missense_variant	4/23	ENST00000392634.9
INF2	NM_001031714.4	c.658G>C	p.Glu220Gln	missense_variant	4/22
INF2	NM_032714.3	c.658G>C	p.Glu220Gln	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.658G>C	p.Glu220Gln	missense_variant	4/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247256 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134872

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459720 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.8	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.5	N;D;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.47
MutPred		0.76		Gain of catalytic residue at L224 (P = 8e-04);Gain of catalytic residue at L224 (P = 8e-04);Gain of catalytic residue at L224 (P = 8e-04);
MVP		0.90
MPC		2.4
ClinPred		0.86	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs530391015; hg19: chr14-105169782;