rs201383094

chr14-104701402-G-Achr14-104701402-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_022489.4(INF2):c.37G>A(p.Ala13Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000355 in 1,593,462 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: INF2 NM_022489.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.50

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09146482).
• BP6: Variant 14-104701402-G-A is Benign according to our data. Variant chr14-104701402-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 312676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000308 (47/152384) while in subpopulation AMR AF= 0.00137 (21/15306). AF 95% confidence interval is 0.000919. There are 1 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INF2	NM_022489.4	c.37G>A	p.Ala13Thr	missense_variant	2/23	ENST00000392634.9
INF2	NM_001031714.4	c.37G>A	p.Ala13Thr	missense_variant	2/22
INF2	NM_032714.3	c.37G>A	p.Ala13Thr	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INF2	ENST00000392634.9	c.37G>A	p.Ala13Thr	missense_variant	2/23	5	NM_022489.4	P4

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152266 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000357 AC: 76 AN: 212926 Hom.: 1 AF XY: 0.000344 AC XY: 40 AN XY: 116412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000874

Gnomad ASJ exome AF: 0.00107

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000366

Gnomad OTH exome AF: 0.000740

GnomAD4 exome AF: 0.000360 AC: 519 AN: 1441078 Hom.: 1 Cov.: 31 AF XY: 0.000376 AC XY: 269 AN XY: 714884

Gnomad4 AFR exome AF: 0.0000605

Gnomad4 AMR exome AF: 0.000723

Gnomad4 ASJ exome AF: 0.00132

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000383

Gnomad4 OTH exome AF: 0.000437

GnomAD4 genome AF: 0.000308 AC: 47 AN: 152384 Hom.: 1 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74516

Gnomad4 AFR AF: 0.0000961

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000361 Hom.: 1

Bravo AF: 0.000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.000266 AC: 32

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	INF2: PP2, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23014460, 20023659, 30295827) -

Focal segmental glomerulosclerosis 5;C4302667:Charcot-Marie-Tooth disease dominant intermediate E Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Focal segmental glomerulosclerosis 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

INF2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Uncertain	0.078	D
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	N;D;N
REVEL	Uncertain	0.64
Sift	Benign	0.066	T;T;D
Sift4G	Benign	0.074	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.14
MVP		0.82
MPC		2.3
ClinPred		0.10	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.82

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: rs201383094; hg19: chr14-105167739;