14-85622223-A-T

Position:

• chr14-85622223-A-T

Variant summary

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

The NM_013231.6(FLRT2):​c.709A>T​(p.Ile237Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLRT2 NM_013231.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75

Genes affected

FLRT2 (HGNC:3761): (fibronectin leucine rich transmembrane protein 2) This gene encodes a member of the fibronectin leucine rich transmembrane (FLRT) family of cell adhesion molecules, which regulate early embryonic vascular and neural development. The encoded type I transmembrane protein has an extracellular region consisting of an N-terminal leucine-rich repeat domain and a type 3 fibronectin domain, followed by a transmembrane domain and a short C-terminal cytoplasmic tail domain. It functions as both a homophilic cell adhesion molecule and a heterophilic chemorepellent through its interaction with members of the uncoordinated-5 receptor family. Proteolytic removal of the extracellular region controls the migration of neurons in the developing cortex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

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	UniProt
FLRT2	NM_013231.6	c.709A>T	p.Ile237Phe	missense_variant	2/2	ENST00000330753.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLRT2	ENST00000330753.6	c.709A>T	p.Ile237Phe	missense_variant	2/2	1	NM_013231.6	P1
FLRT2	ENST00000554746.1	c.709A>T	p.Ile237Phe	missense_variant	2/2	1		P1
FLRT2	ENST00000682132.1	c.709A>T	p.Ile237Phe	missense_variant	2/2			P1
FLRT2	ENST00000683129.1	c.709A>T	p.Ile237Phe	missense_variant	2/2			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

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

Apr 24, 2023

The c.709A>T (p.I237F) alteration is located in exon 2 (coding exon 1) of the FLRT2 gene. This alteration results from a A to T substitution at nucleotide position 709, causing the isoleucine (I) at amino acid position 237 to be replaced by a phenylalanine (F). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.0090	B;B
Vest4		0.65
MutPred		0.61		Loss of ubiquitination at K233 (P = 0.0683);Loss of ubiquitination at K233 (P = 0.0683);
MVP		0.54
MPC		0.75
ClinPred		0.53	D
GERP RS		5.8
Varity_R		0.18
gMVP		0.65

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: chr14-86088567;