chr17-45240621-C-T

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

2
16

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

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
FMNL1NM_005892.4 linkc.1226C>T p.Ala409Val missense_variant Exon 12 of 27 ENST00000331495.8 NP_005883.3 O95466-1
FMNL1NM_001411128.1 linkc.1226C>T p.Ala409Val missense_variant Exon 12 of 26 NP_001398057.1
FMNL1-AS1NR_186807.1 linkn.825+325G>A intron_variant Intron 1 of 1
FMNL1-AS1NR_186808.1 linkn.661-17G>A intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FMNL1ENST00000331495.8 linkc.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:
26
AN:
152196
Hom.:
0
Cov.:
32
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.:
0
AF XY:
0.000697
AC XY:
94
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.:
3
Cov.:
31
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:
26
AN:
152314
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
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.:
0
Bravo
AF:
0.0000718
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000610
AC:
74
Asia WGS
AF:
0.00115
AC:
4
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
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;T
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.39
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.81
T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.0058
T;T
MetaSVM
Benign
-0.50
T
PrimateAI
Benign
0.36
T
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
T
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.

Other links and lift over

dbSNP: rs146321570; hg19: chr17-43317988; API