14-85622899-T-C

Variant summary

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

The NM_013231.6(FLRT2):c.1385T>C(p.Val462Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: FLRT2 NM_013231.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60

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 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=0.056418628).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLRT2	NM_013231.6	c.1385T>C	p.Val462Ala	missense_variant	2/2	ENST00000330753.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLRT2	ENST00000330753.6	c.1385T>C	p.Val462Ala	missense_variant	2/2	1	NM_013231.6	P1
FLRT2	ENST00000554746.1	c.1385T>C	p.Val462Ala	missense_variant	2/2	1		P1
FLRT2	ENST00000682132.1	c.1385T>C	p.Val462Ala	missense_variant	2/2			P1
FLRT2	ENST00000683129.1	c.1385T>C	p.Val462Ala	missense_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251364 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000205 AC: 300 AN: 1461884 Hom.: 0 Cov.: 36 AF XY: 0.000213 AC XY: 155 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000252

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000327

EpiControl AF: 0.000178

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

Jun 06, 2023

The c.1385T>C (p.V462A) alteration is located in exon 2 (coding exon 1) of the FLRT2 gene. This alteration results from a T to C substitution at nucleotide position 1385, causing the valine (V) at amino acid position 462 to be replaced by an alanine (A). 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	0.071
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	18
Dann	Benign	0.50
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.060	N;N
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.72	N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.089	B;B
Vest4		0.33
MVP		0.34
MPC		0.36
ClinPred		0.063	T
GERP RS		6.2
Varity_R		0.054
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs139260862; hg19: chr14-86089243;