Genetic Variant FMNL2:p.Ser169Ile (chr2-152560945-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_052905.4(FMNL2):c.506G>T(p.Ser169Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000744 in 1,343,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

FMNL2
NM_052905.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.59

Publications

0 publications found

Variant links:

Genes affected

FMNL2 (HGNC:18267): (formin like 2) This gene encodes a formin-related protein. Formin-related proteins have been implicated in morphogenesis, cytokinesis, and cell polarity. Alternatively spliced transcript variants encoding different isoforms have been described but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

FMNL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FMNL2	NM_052905.4 link	c.506G>T	p.Ser169Ile	missense_variant	Exon 6 of 26	ENST00000288670.14	NP_443137.2	Q96PY5-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FMNL2	ENST00000288670.14 link	c.506G>T	p.Ser169Ile	missense_variant	Exon 6 of 26	1	NM_052905.4	ENSP00000288670.9		Q96PY5-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.44e-7

AC:

AN:

1343608

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

663780

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29930

American (AMR)

AF:

0.00

AC:

AN:

37920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23458

East Asian (EAS)

AF:

0.00

AC:

AN:

34222

South Asian (SAS)

AF:

0.00

AC:

AN:

63554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5376

European-Non Finnish (NFE)

AF:

9.55e-7

AC:

AN:

1046722

Other (OTH)

AF:

0.00

AC:

AN:

54536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.506G>T (p.S169I) alteration is located in exon 6 (coding exon 6) of the FMNL2 gene. This alteration results from a G to T substitution at nucleotide position 506, causing the serine (S) at amino acid position 169 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

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.7

PhyloP100

7.6

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.71

Sift

Benign

0.077

Sift4G

Benign

0.072

Polyphen

0.99

Vest4

0.81

MutPred

0.51

Loss of phosphorylation at S169 (P = 0.0085);

MVP

0.78

MPC

0.90

ClinPred

0.99

GERP RS

4.8

gMVP

0.62

Mutation Taster

=77/23

polymorphism

(source)

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

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2-152560945-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over