17-18245821-G-T

Position:

• chr17-18245821-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002018.4(FLII):​c.3426C>A​(p.Asn1142Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.62

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLII	NM_002018.4	c.3426C>A	p.Asn1142Lys	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.3426C>A	p.Asn1142Lys	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.3426C>A (p.N1142K) alteration is located in exon 27 (coding exon 27) of the FLII gene. This alteration results from a C to A substitution at nucleotide position 3426, causing the asparagine (N) at amino acid position 1142 to be replaced by a lysine (K). 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	Pathogenic	1.0
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;D;.;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.7	.;M;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.3	.;D;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.088	.;T;.;.;.
Sift4G	Pathogenic	0.0	D;T;T;T;D
Polyphen		0.49	.;P;.;.;.
Vest4		0.86, 0.87, 0.87
MutPred		0.58		.;Gain of methylation at N1142 (P = 0.0011);.;.;.;
MVP		0.75
MPC		1.0
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.63
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr17-18149135;