Genetic Variant FMNL1:p.Thr523Ile (chr17-45241617-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.1568C>T(p.Thr523Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,519,114 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 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

FMNL1
NM_005892.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.257

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=0.016135037).

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMNL1	NM_005892.4 link	c.1568C>T	p.Thr523Ile	missense_variant	Exon 14 of 27	ENST00000331495.8	NP_005883.3	O95466-1
FMNL1	NM_001411128.1 link	c.1568C>T	p.Thr523Ile	missense_variant	Exon 14 of 26		NP_001398057.1
FMNL1-AS1	NR_186807.1 link	n.154G>A		non_coding_transcript_exon_variant	Exon 1 of 2
FMNL1-AS1	NR_186808.1 link	n.154G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FMNL1	ENST00000331495.8 link	c.1568C>T	p.Thr523Ile	missense_variant	Exon 14 of 27	1	NM_005892.4	ENSP00000329219.2	O95466-1
FMNL1	ENST00000587489.6 link	c.1568C>T	p.Thr523Ile	missense_variant	Exon 14 of 26	1		ENSP00000465474.2	O95466-2K7EK60
FMNL1-AS1	ENST00000587534.1 link	n.118G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
FMNL1	ENST00000587856.1 link	n.1925C>T		non_coding_transcript_exon_variant	Exon 7 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000314

AC:

AN:

136742

Hom.:

AF XY:

0.000230

AC XY:

AN XY:

73942

show subpopulations

Gnomad AFR exome

AF:

0.000338

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000562

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000367

Gnomad OTH exome

AF:

0.00139

GnomAD4 exome

AF:

0.000203

AC:

277

AN:

1366864

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

147

AN XY:

670812

show subpopulations

Gnomad4 AFR exome

AF:

0.000255

Gnomad4 AMR exome

AF:

0.000670

Gnomad4 ASJ exome

AF:

0.0000449

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000663

Gnomad4 FIN exome

AF:

0.0000232

Gnomad4 NFE exome

AF:

0.000188

Gnomad4 OTH exome

AF:

0.000391

GnomAD4 genome

AF:

0.000276

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000510

Hom.:

Bravo

AF:

0.000276

ExAC

AF:

0.000141

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1568C>T (p.T523I) alteration is located in exon 14 (coding exon 14) of the FMNL1 gene. This alteration results from a C to T substitution at nucleotide position 1568, causing the threonine (T) at amino acid position 523 to be replaced by an isoleucine (I). 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

0.090

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.7

DANN

Benign

0.92

DEOGEN2

Benign

0.045

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.45

T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-0.83

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.6

N;.;.

REVEL

Benign

0.20

Sift

Benign

0.11

T;.;.

Sift4G

Benign

0.25

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.044

MVP

0.19

MPC

0.62

ClinPred

0.0050

GERP RS

2.2

Varity_R

0.059

gMVP

0.10

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