rs761806103

Positions:

• chr14-104707033-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_022489.4(INF2):​c.967G>A​(p.Val323Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000908 in 1,431,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INF2	NM_022489.4	c.967G>A	p.Val323Met	missense_variant	7/23	ENST00000392634.9	NP_071934.3
INF2	NM_001031714.4	c.967G>A	p.Val323Met	missense_variant	7/22		NP_001026884.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INF2	ENST00000392634.9	c.967G>A	p.Val323Met	missense_variant	7/23	5	NM_022489.4	ENSP00000376410	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000498 AC: 1 AN: 200880 Hom.: 0 AF XY: 0.00000898 AC XY: 1 AN XY: 111388

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: 0.0000371

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000908 AC: 13 AN: 1431646 Hom.: 0 Cov.: 33 AF XY: 0.0000112 AC XY: 8 AN XY: 711128

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000905

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000168 AC: 2

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

May 17, 2023

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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on INF2 protein function. ClinVar contains an entry for this variant (Variation ID: 540053). This variant has not been reported in the literature in individuals affected with INF2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 323 of the INF2 protein (p.Val323Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		1.0	D;D
Vest4		0.34
MutPred		0.48		Gain of catalytic residue at V319 (P = 0.0018);Gain of catalytic residue at V319 (P = 0.0018);
MVP		0.67
MPC		0.89
ClinPred		0.73	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.76

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: rs761806103; hg19: chr14-105173370;