Genetic Variant NM_001277313.2:c.4204A>G (chr15-32776846-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001277313.2(FMN1):c.4204A>G(p.Thr1402Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000549 in 1,583,520 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000056 ( 1 hom. )

Consequence

FMN1
NM_001277313.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.87

Variant links:

Genes affected

FMN1 (HGNC:3768): (formin 1) This gene belongs to the formin homology family and encodes a protein that has a role in the formation of adherens junction and the polymerization of linear actin cables. The homologous gene in mouse is associated with limb deformity. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2015]

FMN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07537848).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMN1	NM_001277313.2 link	c.4204A>G	p.Thr1402Ala	missense_variant	Exon 20 of 21	ENST00000616417.5	NP_001264242.1	Q68DA7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMN1	ENST00000616417.5 link	c.4204A>G	p.Thr1402Ala	missense_variant	Exon 20 of 21	5	NM_001277313.2	ENSP00000479134.1		Q68DA7-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000633

AC:

AN:

221188

Hom.:

AF XY:

0.0000929

AC XY:

AN XY:

118408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000159

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000921

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000559

AC:

AN:

1431426

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

710404

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.0000714

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000485

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000605

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1179 of the FMN1 protein (p.Thr1179Ala). This variant is present in population databases (rs774106707, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FMN1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.40

DEOGEN2

Benign

0.12

T;.;T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.84

M_CAP

Benign

0.0035

MetaRNN

Benign

0.075

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;.;.;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.5

.;N;N;N

REVEL

Benign

0.071

Sift

Benign

0.22

.;T;T;T

Sift4G

Benign

0.76

T;T;T;T

Polyphen

0.15

.;B;.;.

Vest4

0.18

MutPred

0.30

.;Loss of phosphorylation at T1179 (P = 0.0585);.;.;

MVP

0.36

MPC

0.035

ClinPred

0.12

GERP RS

1.7

Varity_R

0.081

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over