17-18245770-C-G

Position:

• chr17-18245770-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002018.4(FLII):​c.3477G>C​(p.Glu1159Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLII NM_002018.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.20

Genes affected

FLII (HGNC:3750): (FLII actin remodeling protein) This gene encodes a protein with a gelsolin-like actin binding domain and an N-terminal leucine-rich repeat-protein protein interaction domain. The protein is similar to a Drosophila protein involved in early embryogenesis and the structural organization of indirect flight muscle. The gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

FLII (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06788787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLII	NM_002018.4	c.3477G>C	p.Glu1159Asp	missense_variant	27/30	ENST00000327031.9	NP_002009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLII	ENST00000327031.9	c.3477G>C	p.Glu1159Asp	missense_variant	27/30	1	NM_002018.4	ENSP00000324573.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2024

The c.3477G>C (p.E1159D) alteration is located in exon 27 (coding exon 27) of the FLII gene. This alteration results from a G to C substitution at nucleotide position 3477, causing the glutamic acid (E) at amino acid position 1159 to be replaced by an aspartic acid (D). 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	0.070
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.2
DANN	Benign	0.67
DEOGEN2	Benign	0.14	.;T;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.068	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.040	.;N;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.26	.;N;.;.;.
REVEL	Benign	0.14
Sift	Benign	0.64	.;T;.;.;.
Sift4G	Benign	0.81	T;T;T;T;T
Polyphen		0.0	.;B;.;.;.
Vest4		0.34, 0.30, 0.34
MutPred		0.33		.;Loss of catalytic residue at E1159 (P = 0.0311);.;.;.;
MVP		0.16
MPC		0.25
ClinPred		0.12	T
GERP RS		-1.9
Varity_R		0.039
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-18149084;