11-64117387-G-C

Position:

chr11-64117387-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013280.5(FLRT1):c.1120G>C(p.Glu374Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000181 in 1,612,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

FLRT1
NM_013280.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.99

Variant links:

Genes affected

FLRT1 (HGNC:3760): (fibronectin leucine rich transmembrane protein 1) This gene encodes a member of the fibronectin leucine rich transmembrane protein (FLRT) family. The family members may function in cell adhesion and/or receptor signalling. Their protein structures resemble small leucine-rich proteoglycans found in the extracellular matrix. The encoded protein shares sequence similarity with two other family members, FLRT2 and FLRT3. This gene is expressed in kidney and brain. [provided by RefSeq, Jul 2008]

FLRT1 links:

MACROD1 (HGNC:29598): (mono-ADP ribosylhydrolase 1) Enables ADP-ribosylglutamate hydrolase activity and deacetylase activity. Involved in cellular response to DNA damage stimulus; peptidyl-glutamate ADP-deribosylation; and purine nucleoside metabolic process. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MACROD1 links:

MACROD1 (HGNC:):

MACROD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13559887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLRT1	NM_013280.5 linkuse as main transcript	c.1120G>C	p.Glu374Gln	missense_variant	3/3	ENST00000682287.1	NP_037412.2	Q9NZU1A0A6E1VY70
MACROD1	NM_014067.4 linkuse as main transcript	c.517+33852C>G		intron_variant		ENST00000255681.7	NP_054786.2	Q9BQ69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLRT1	ENST00000682287.1 linkuse as main transcript	c.1120G>C	p.Glu374Gln	missense_variant	3/3		NM_013280.5	ENSP00000507207.1		A0A6E1VY70
MACROD1	ENST00000255681.7 linkuse as main transcript	c.517+33852C>G		intron_variant		1	NM_014067.4	ENSP00000255681.6		Q9BQ69

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000220

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000120

AC:

AN:

250404

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

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:

0.000247

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000188

AC:

275

AN:

1459820

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

128

AN XY:

725832

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000241

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000112

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000140

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.1120G>C (p.E374Q) alteration is located in exon 2 (coding exon 1) of the FLRT1 gene. This alteration results from a G to C substitution at nucleotide position 1120, causing the glutamic acid (E) at amino acid position 374 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Peripheral neuropathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 07, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with FLRT1-related disease. This variant is present in population databases (rs138445479, ExAC 0.03%). This sequence change replaces glutamic acid with glutamine at codon 374 of the FLRT1 protein (p.Glu374Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

0.022

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.054

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.98

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.78

REVEL

Benign

0.057

Sift

Benign

0.18

Sift4G

Benign

0.26

Vest4

0.13

MVP

0.44

MPC

0.36

ClinPred

0.063

GERP RS

5.1

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over