Genetic Variant FMNL1:p.Ala409Val (chr17-45240621-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005892.4(FMNL1):c.1226C>T(p.Ala409Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,612,920 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 3 hom. )

Consequence

FMNL1
NM_005892.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

Variant links:

Genes affected

FMNL1 (HGNC:1212): (formin like 1) This gene encodes a formin-related protein. Formin-related proteins have been implicated in morphogenesis, cytokinesis, and cell polarity. An alternative splice variant has been described but its full length sequence has not been determined. [provided by RefSeq, Jul 2008]

FMNL1 links:

FMNL1-AS1 (HGNC:55717): (FMNL1 antisense RNA 1)

FMNL1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057687163).

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMNL1	NM_005892.4 link	c.1226C>T	p.Ala409Val	missense_variant	Exon 12 of 27	ENST00000331495.8	NP_005883.3	O95466-1
FMNL1	NM_001411128.1 link	c.1226C>T	p.Ala409Val	missense_variant	Exon 12 of 26		NP_001398057.1
FMNL1-AS1	NR_186807.1 link	n.825+325G>A		intron_variant	Intron 1 of 1
FMNL1-AS1	NR_186808.1 link	n.661-17G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMNL1	ENST00000331495.8 link	c.1226C>T	p.Ala409Val	missense_variant	Exon 12 of 27	1	NM_005892.4	ENSP00000329219.2		O95466-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000525

AC:

131

AN:

249588

Hom.:

AF XY:

0.000697

AC XY:

AN XY:

134908

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00397

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000710

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000305

AC:

445

AN:

1460606

Hom.:

Cov.:

AF XY:

0.000398

AC XY:

289

AN XY:

726568

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00389

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000801

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000171

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000146

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1226C>T (p.A409V) alteration is located in exon 12 (coding exon 12) of the FMNL1 gene. This alteration results from a C to T substitution at nucleotide position 1226, causing the alanine (A) at amino acid position 409 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.81

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0058

T;T

MetaSVM

Benign

-0.50

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.23

Sift

Benign

0.060

T;.

Sift4G

Benign

0.36

T;T

Polyphen

0.24

B;.

Vest4

0.14

MVP

0.61

MPC

0.58

ClinPred

0.045

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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