1-240207469-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020066.5(FMN2):c.2657T>G(p.Met886Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,611,902 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 9 hom., cov: 30)

Exomes 𝑓: 0.0067 ( 40 hom. )

Consequence

FMN2
NM_020066.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.247

Publications

4 publications found

Variant links:

Genes affected

FMN2 (HGNC:14074): (formin 2) This gene is a member of the formin homology protein family. The encoded protein is thought to have essential roles in organization of the actin cytoskeleton and in cell polarity. This protein mediates the formation of an actin mesh that positions the spindle during oogenesis and also regulates the formation of actin filaments in the nucleus. This protein also forms a perinuclear actin/focal-adhesion system that regulates the shape and position of the nucleus during cell migration. Mutations in this gene have been associated with infertility and also with an autosomal recessive form of intellectual disability (MRT47). Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jul 2017]

FMN2 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 47
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FMN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032209456).

BP6

Variant 1-240207469-T-G is Benign according to our data. Variant chr1-240207469-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00537 (807/150396) while in subpopulation NFE AF = 0.00713 (481/67492). AF 95% confidence interval is 0.0066. There are 9 homozygotes in GnomAd4. There are 408 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMN2	NM_020066.5 link	c.2657T>G	p.Met886Arg	missense_variant	Exon 5 of 18	ENST00000319653.14	NP_064450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMN2	ENST00000319653.14 link	c.2657T>G	p.Met886Arg	missense_variant	Exon 5 of 18	5	NM_020066.5	ENSP00000318884.9

Frequencies

GnomAD3 genomes

AF:

0.00537

AC:

807

AN:

150276

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000933

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00132

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.000201

Gnomad SAS

AF:

0.00127

Gnomad FIN

AF:

0.0240

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00713

Gnomad OTH

AF:

0.00289

GnomAD2 exomes

AF:

0.00579

AC:

1454

AN:

251062

AF XY:

0.00598

show subpopulations

Gnomad AFR exome

AF:

0.000801

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.000599

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0214

Gnomad NFE exome

AF:

0.00707

Gnomad OTH exome

AF:

0.00702

GnomAD4 exome

AF:

0.00670

AC:

9786

AN:

1461506

Hom.:

Cov.:

AF XY:

0.00661

AC XY:

4808

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33478

American (AMR)

AF:

0.00179

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000575

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00231

AC:

199

AN:

86254

European-Finnish (FIN)

AF:

0.0239

AC:

1278

AN:

53408

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00700

AC:

7778

AN:

1111736

Other (OTH)

AF:

0.00658

AC:

397

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

653

1306

1959

2612

3265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

278

556

834

1112

1390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00537

AC:

807

AN:

150396

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

408

AN XY:

73460

show subpopulations

African (AFR)

AF:

0.000930

AC:

AN:

40854

American (AMR)

AF:

0.00132

AC:

AN:

15138

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3462

East Asian (EAS)

AF:

0.000201

AC:

AN:

4972

South Asian (SAS)

AF:

0.00127

AC:

AN:

4706

European-Finnish (FIN)

AF:

0.0240

AC:

251

AN:

10478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00713

AC:

481

AN:

67492

Other (OTH)

AF:

0.00286

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00574

Hom.:

Bravo

AF:

0.00352

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00627

AC:

761

EpiCase

AF:

0.00567

EpiControl

AF:

0.00534

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FMN2: BP4, BS2 -

Feb 17, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FMN2-related disorder

Benign:1

Apr 01, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as 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

0.13

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.5

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.070

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

PhyloP100

-0.25

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.0

REVEL

Benign

0.015

Sift

Uncertain

0.010

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.33

MVP

0.33

MPC

0.14

ClinPred

0.0050

GERP RS

-0.30

Varity_R

0.40

gMVP

0.28

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over