Genetic Variant NM_020066.5:c.2823A>T (chr1-240207635-A-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP7

The NM_020066.5(FMN2):c.2823A>T(p.Gly941Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G941G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000023 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FMN2
NM_020066.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.845

Publications

5 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP7

Synonymous conserved (PhyloP=-0.845 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMN2	NM_020066.5 link	c.2823A>T	p.Gly941Gly	synonymous_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.2823A>T	p.Gly941Gly	synonymous_variant	Exon 5 of 18	5	NM_020066.5	ENSP00000318884.9		Q9NZ56-1

Frequencies

GnomAD3 genomes

AF:

0.0000226

AC:

AN:

44266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000430

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

868674

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

425156

African (AFR)

AF:

0.00

AC:

AN:

14866

American (AMR)

AF:

0.00

AC:

AN:

27314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8928

East Asian (EAS)

AF:

0.00

AC:

AN:

12412

South Asian (SAS)

AF:

0.00

AC:

AN:

43538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24718

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1992

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

704680

Other (OTH)

AF:

0.00

AC:

AN:

30226

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000226

AC:

AN:

44266

Hom.:

Cov.:

AF XY:

0.0000471

AC XY:

AN XY:

21232

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

9398

American (AMR)

AF:

0.00

AC:

AN:

4552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

820

East Asian (EAS)

AF:

0.00

AC:

AN:

1372

South Asian (SAS)

AF:

0.00

AC:

AN:

1258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000430

AC:

AN:

23232

Other (OTH)

AF:

0.00

AC:

AN:

590

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.61

(source)

DANN

Benign

0.30

PhyloP100

-0.84

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over