Genetic Variant FMNL1:p.Pro519Leu (chr17-45241605-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005892.4(FMNL1):c.1556C>T(p.Pro519Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000352 in 1,532,420 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

FMNL1
NM_005892.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0900

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10743824).

BS2

High AC in GnomAdExome4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMNL1	NM_005892.4 link	c.1556C>T	p.Pro519Leu	missense_variant	Exon 14 of 27	ENST00000331495.8	NP_005883.3	O95466-1
FMNL1	NM_001411128.1 link	c.1556C>T	p.Pro519Leu	missense_variant	Exon 14 of 26		NP_001398057.1
FMNL1-AS1	NR_186807.1 link	n.166G>A		non_coding_transcript_exon_variant	Exon 1 of 2
FMNL1-AS1	NR_186808.1 link	n.166G>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.1556C>T	p.Pro519Leu	missense_variant	Exon 14 of 27	1	NM_005892.4	ENSP00000329219.2	O95466-1
FMNL1	ENST00000587489.6 link	c.1556C>T	p.Pro519Leu	missense_variant	Exon 14 of 26	1		ENSP00000465474.2	O95466-2K7EK60
FMNL1-AS1	ENST00000587534.1 link	n.130G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
FMNL1	ENST00000587856.1 link	n.1913C>T		non_coding_transcript_exon_variant	Exon 7 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

148830

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

80730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000411

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:

0.0000337

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000362

AC:

AN:

1380286

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

678950

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000281

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000222

Gnomad4 NFE exome

AF:

0.0000440

Gnomad4 OTH exome

AF:

0.0000176

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1556C>T (p.P519L) 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 1556, causing the proline (P) at amino acid position 519 to be replaced by a leucine (L). 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

0.072

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.050

T;T;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.66

T;T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.87

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

N;.;.

REVEL

Benign

0.25

Sift

Benign

0.39

T;.;.

Sift4G

Benign

0.10

T;D;D

Polyphen

0.0020

B;.;.

Vest4

0.12

MVP

0.21

MPC

0.59

ClinPred

0.13

GERP RS

2.2

Varity_R

0.071

gMVP

0.16

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