chr20-14326378-C-T

Position:

chr20-14326378-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198391.3(FLRT3):c.1129G>A(p.Ala377Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,613,912 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 32)

Exomes 𝑓: 0.011 ( 118 hom. )

Consequence

FLRT3
NM_198391.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.25

Variant links:

Genes affected

FLRT3 (HGNC:3762): (fibronectin leucine rich transmembrane protein 3) This gene encodes a member of the fibronectin leucine rich transmembrane protein (FLRT) family. FLRTs may function in cell adhesion and/or receptor signalling. Their protein structures resemble small leucine-rich proteoglycans found in the extracellular matrix. This gene is expressed in many tissues. Two alternatively spliced transcript variants encoding the same protein have been described for this gene. [provided by RefSeq, Jul 2010]

FLRT3 links:

MACROD2 (HGNC:16126): (mono-ADP ribosylhydrolase 2) The protein encoded by this gene is a deacetylase involved in removing ADP-ribose from mono-ADP-ribosylated proteins. The encoded protein has been shown to translocate from the nucleus to the cytoplasm upon DNA damage. [provided by RefSeq, May 2017]

MACROD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016800463).

BP6

Variant 20-14326378-C-T is Benign according to our data. Variant chr20-14326378-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.015 (2289/152224) while in subpopulation AFR AF= 0.0269 (1118/41552). AF 95% confidence interval is 0.0256. There are 24 homozygotes in gnomad4. There are 1106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2289 AD,Digenic,Multigenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLRT3	NM_198391.3 link	c.1129G>A	p.Ala377Thr	missense_variant	3/3	ENST00000341420.5	NP_938205.1	Q9NZU0
MACROD2	NM_001351661.2 link	c.272-167101C>T		intron_variant		ENST00000684519.1	NP_001338590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLRT3	ENST00000341420.5 link	c.1129G>A	p.Ala377Thr	missense_variant	3/3	2	NM_198391.3	ENSP00000339912.4		Q9NZU0
MACROD2	ENST00000684519.1 link	c.272-167101C>T		intron_variant			NM_001351661.2	ENSP00000507484.1		A1Z1Q3-1

Frequencies

GnomAD3 genomes

AF:

0.0151

AC:

2290

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0270

Gnomad AMI

AF:

0.0746

Gnomad AMR

AF:

0.00754

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00907

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.00970

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0110

AC:

2766

AN:

250884

Hom.:

AF XY:

0.0102

AC XY:

1377

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0284

Gnomad AMR exome

AF:

0.00512

Gnomad ASJ exome

AF:

0.00388

Gnomad EAS exome

AF:

0.00974

Gnomad SAS exome

AF:

0.0114

Gnomad FIN exome

AF:

0.0104

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0108

GnomAD4 exome

AF:

0.0113

AC:

16555

AN:

1461688

Hom.:

118

Cov.:

AF XY:

0.0111

AC XY:

8090

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.0266

Gnomad4 AMR exome

AF:

0.00573

Gnomad4 ASJ exome

AF:

0.00360

Gnomad4 EAS exome

AF:

0.00673

Gnomad4 SAS exome

AF:

0.0116

Gnomad4 FIN exome

AF:

0.00998

Gnomad4 NFE exome

AF:

0.0115

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.0150

AC:

2289

AN:

152224

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1106

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0269

Gnomad4 AMR

AF:

0.00747

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.00909

Gnomad4 SAS

AF:

0.0114

Gnomad4 FIN

AF:

0.00970

Gnomad4 NFE

AF:

0.0109

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0108

Hom.:

Bravo

AF:

0.0151

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0130

AC:

ESP6500AA

AF:

0.0261

AC:

115

ESP6500EA

AF:

0.00872

AC:

ExAC

AF:

0.0114

AC:

1388

Asia WGS

AF:

0.0150

AC:

AN:

3476

EpiCase

AF:

0.0107

EpiControl

AF:

0.00960

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	This variant is associated with the following publications: (PMID: 29767709) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	FLRT3: BP4, BS1, BS2; MACROD2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.020

T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

.;D

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

1.0

N;N

REVEL

Benign

0.23

Sift

Benign

0.57

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.030

MPC

0.38

ClinPred

0.026

GERP RS

6.1

Varity_R

0.072

gMVP

0.47

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