Genetic Variant FMNL1:p.Pro547Arg (chr17-45241901-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005892.4(FMNL1):c.1640C>G(p.Pro547Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,266,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P547Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

FMNL1
NM_005892.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.07

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20049459).

BS2

High AC in GnomAdExome4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005892.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FMNL1	NM_005892.4	MANE Select	c.1640C>G	p.Pro547Arg	missense	Exon 15 of 27	NP_005883.3
FMNL1	NM_001411128.1		c.1640C>G	p.Pro547Arg	missense	Exon 15 of 26	NP_001398057.1	O95466-2
FMNL1-AS1	NR_186807.1		n.-131G>C		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FMNL1	ENST00000331495.8	TSL:1 MANE Select	c.1640C>G	p.Pro547Arg	missense	Exon 15 of 27	ENSP00000329219.2	O95466-1
FMNL1	ENST00000587489.6	TSL:1	c.1640C>G	p.Pro547Arg	missense	Exon 15 of 26	ENSP00000465474.2	K7EK60
FMNL1	ENST00000947279.1		c.1658C>G	p.Pro553Arg	missense	Exon 17 of 28	ENSP00000617338.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

28850

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000111

AC:

AN:

1266788

Hom.:

Cov.:

AF XY:

0.0000177

AC XY:

AN XY:

620496

show subpopulations

African (AFR)

AF:

0.0000406

AC:

AN:

24638

American (AMR)

AF:

0.00

AC:

AN:

17192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19042

East Asian (EAS)

AF:

0.00

AC:

AN:

28854

South Asian (SAS)

AF:

0.00

AC:

AN:

62950

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3590

European-Non Finnish (NFE)

AF:

0.0000127

AC:

AN:

1027576

Other (OTH)

AF:

0.00

AC:

AN:

52234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.38

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.49

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.1

PhyloP100

2.1

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.054

Sift

Benign

0.082

Sift4G

Uncertain

0.0030

Polyphen

0.62

Vest4

0.36

MutPred

0.27

Loss of glycosylation at P547 (P = 0.0061)

MVP

0.20

MPC

0.61

ClinPred

0.42

GERP RS

3.2

Varity_R

0.098

gMVP

0.20

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over