rs147858483

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.778G>A(p.Ala260Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,517,818 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A260V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0090 ( 18 hom., cov: 33)

Exomes 𝑓: 0.00077 ( 19 hom. )

Consequence

FMN2
NM_020066.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.324

Publications

1 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=0.0028507411).

BP6

Variant 1-240092887-G-A is Benign according to our data. Variant chr1-240092887-G-A is described in ClinVar as Benign. ClinVar VariationId is 377373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00903 (1375/152216) while in subpopulation AFR AF = 0.031 (1289/41568). AF 95% confidence interval is 0.0296. There are 18 homozygotes in GnomAd4. There are 666 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMN2	NM_020066.5 link	c.778G>A	p.Ala260Thr	missense_variant	Exon 1 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.778G>A	p.Ala260Thr	missense_variant	Exon 1 of 18	5	NM_020066.5	ENSP00000318884.9
FMN2	ENST00000447095.5 link	c.-87+24814G>A		intron_variant	Intron 2 of 6	3		ENSP00000409308.1

Frequencies

GnomAD3 genomes

AF:

0.00897

AC:

1365

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0309

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00718

GnomAD2 exomes

AF:

0.00218

AC:

242

AN:

111134

AF XY:

0.00192

show subpopulations

Gnomad AFR exome

AF:

0.0304

Gnomad AMR exome

AF:

0.00207

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000102

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.000770

AC:

1052

AN:

1365602

Hom.:

Cov.:

AF XY:

0.000678

AC XY:

456

AN XY:

672450

show subpopulations

African (AFR)

AF:

0.0266

AC:

821

AN:

30912

American (AMR)

AF:

0.00194

AC:

AN:

32456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23472

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35626

South Asian (SAS)

AF:

0.0000396

AC:

AN:

75732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35372

Middle Eastern (MID)

AF:

0.000750

AC:

AN:

4002

European-Non Finnish (NFE)

AF:

0.0000579

AC:

AN:

1071326

Other (OTH)

AF:

0.00175

AC:

AN:

56704

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00903

AC:

1375

AN:

152216

Hom.:

Cov.:

AF XY:

0.00895

AC XY:

666

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0310

AC:

1289

AN:

41568

American (AMR)

AF:

0.00405

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67992

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00394

Hom.:

Bravo

AF:

0.00958

ESP6500AA

AF:

0.0149

AC:

ESP6500EA

AF:

0.000338

AC:

ExAC

AF:

0.000860

AC:

Asia WGS

AF:

0.00145

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 30, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.5

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.065

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.38

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.32

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.89

REVEL

Benign

0.026

Sift

Benign

0.29

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.083

MVP

0.40

MPC

0.77

ClinPred

0.0019

GERP RS

-5.5

Varity_R

0.034

gMVP

0.062

Mutation Taster

=98/2

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