14-85622688-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_013231.6(FLRT2):c.1174A>G(p.Ser392Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,613,936 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: FLRT2 NM_013231.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.13

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003712356).
• BP6: Variant 14-85622688-A-G is Benign according to our data. Variant chr14-85622688-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 711387.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLRT2	NM_013231.6	c.1174A>G	p.Ser392Gly	missense_variant	2/2	ENST00000330753.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLRT2	ENST00000330753.6	c.1174A>G	p.Ser392Gly	missense_variant	2/2	1	NM_013231.6	P1
FLRT2	ENST00000554746.1	c.1174A>G	p.Ser392Gly	missense_variant	2/2	1		P1
FLRT2	ENST00000682132.1	c.1174A>G	p.Ser392Gly	missense_variant	2/2			P1
FLRT2	ENST00000683129.1	c.1174A>G	p.Ser392Gly	missense_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 151990 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00510

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00142 AC: 356 AN: 251386 Hom.: 2 AF XY: 0.00149 AC XY: 202 AN XY: 135874

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00565

Gnomad NFE exome AF: 0.00193

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00107 AC: 1566 AN: 1461828 Hom.: 8 Cov.: 36 AF XY: 0.00111 AC XY: 809 AN XY: 727216

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00517

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152108 Hom.: 1 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74366

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00510

Gnomad4 NFE AF: 0.00212

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.000793

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00156 AC: 189

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	5.9
Dann	Benign	0.19
DEOGEN2	Benign	0.059	T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;N
MutationTaster	Benign	0.89	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.068
Sift	Benign	0.63	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0	B;B
Vest4		0.053
MVP		0.42
MPC		0.27
ClinPred		0.017	T
GERP RS		2.6
Varity_R		0.021
gMVP		0.23

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: rs137990800; hg19: chr14-86089032;