NM_020066.5:c.2855C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_020066.5(FMN2):c.2855C>G(p.Ala952Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A952A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0064 ( 1 hom., cov: 11)

Exomes 𝑓: 0.0063 ( 202 hom. )

Failed GnomAD Quality Control

Consequence

FMN2
NM_020066.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.13

Publications

8 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005420178).

BP6

Variant 1-240207667-C-G is Benign according to our data. Variant chr1-240207667-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 377218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMN2	NM_020066.5 link	c.2855C>G	p.Ala952Gly	missense_variant	Exon 5 of 18	ENST00000319653.14	NP_064450.3	Q9NZ56-1Q9HBL1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMN2	ENST00000319653.14 link	c.2855C>G	p.Ala952Gly	missense_variant	Exon 5 of 18	5	NM_020066.5	ENSP00000318884.9		Q9NZ56-1

Frequencies

GnomAD3 genomes

AF:

0.00644

AC:

372

AN:

57762

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00428

Gnomad AMI

AF:

0.00465

Gnomad AMR

AF:

0.00376

Gnomad ASJ

AF:

0.00504

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0230

Gnomad FIN

AF:

0.00620

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00753

Gnomad OTH

AF:

0.00264

GnomAD2 exomes

AF:

0.00524

AC:

1112

AN:

212370

AF XY:

0.00613

show subpopulations

Gnomad AFR exome

AF:

0.00272

Gnomad AMR exome

AF:

0.00224

Gnomad ASJ exome

AF:

0.00223

Gnomad EAS exome

AF:

0.00208

Gnomad FIN exome

AF:

0.00380

Gnomad NFE exome

AF:

0.00387

Gnomad OTH exome

AF:

0.00434

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00632

AC:

7100

AN:

1123696

Hom.:

202

Cov.:

AF XY:

0.00708

AC XY:

3961

AN XY:

559778

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00452

AC:

109

AN:

24122

American (AMR)

AF:

0.00531

AC:

178

AN:

33550

Ashkenazi Jewish (ASJ)

AF:

0.0146

AC:

275

AN:

18786

East Asian (EAS)

AF:

0.0140

AC:

330

AN:

23620

South Asian (SAS)

AF:

0.0213

AC:

1474

AN:

69206

European-Finnish (FIN)

AF:

0.00791

AC:

300

AN:

37934

Middle Eastern (MID)

AF:

0.0134

AC:

AN:

3200

European-Non Finnish (NFE)

AF:

0.00460

AC:

4001

AN:

869640

Other (OTH)

AF:

0.00894

AC:

390

AN:

43638

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.359

Heterozygous variant carriers

379

757

1136

1514

1893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00643

AC:

372

AN:

57810

Hom.:

Cov.:

AF XY:

0.00599

AC XY:

169

AN XY:

28226

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00427

AC:

AN:

13118

American (AMR)

AF:

0.00376

AC:

AN:

5584

Ashkenazi Jewish (ASJ)

AF:

0.00504

AC:

AN:

1190

East Asian (EAS)

AF:

0.00231

AC:

AN:

1730

South Asian (SAS)

AF:

0.0229

AC:

AN:

1484

European-Finnish (FIN)

AF:

0.00620

AC:

AN:

3710

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00753

AC:

224

AN:

29732

Other (OTH)

AF:

0.00262

AC:

AN:

762

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0176

Hom.:

ExAC

AF:

0.00439

AC:

528

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 09, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.17

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.046

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00077

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.61

PhyloP100

-3.1

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.69

REVEL

Benign

0.052

Sift

Benign

1.0

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.074

MVP

0.56

MPC

0.092

ClinPred

0.0014

GERP RS

-2.0

Varity_R

0.030

gMVP

0.091

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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