20-14326373-T-G

Position:

chr20-14326373-T-G

Variant summary

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

The NM_198391.3(FLRT3):c.1134A>C(p.Gln378His) variant causes a missense change. The variant allele was found at a frequency of 0.0235 in 1,613,962 control chromosomes in the GnomAD database, including 587 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 46 hom., cov: 32)

Exomes 𝑓: 0.024 ( 541 hom. )

Consequence

FLRT3
NM_198391.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.97

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=0.004434198).

BP6

Variant 20-14326373-T-G is Benign according to our data. Variant chr20-14326373-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1317710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-14326373-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2724/152276) while in subpopulation NFE AF= 0.0277 (1885/68020). AF 95% confidence interval is 0.0267. There are 46 homozygotes in gnomad4. There are 1299 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2724 AD,Digenic,Multigenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLRT3	NM_198391.3 linkuse as main transcript	c.1134A>C	p.Gln378His	missense_variant	3/3	ENST00000341420.5	NP_938205.1
MACROD2	NM_001351661.2 linkuse as main transcript	c.272-167106T>G		intron_variant		ENST00000684519.1	NP_001338590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLRT3	ENST00000341420.5 linkuse as main transcript	c.1134A>C	p.Gln378His	missense_variant	3/3	2	NM_198391.3	ENSP00000339912	P1
MACROD2	ENST00000684519.1 linkuse as main transcript	c.272-167106T>G		intron_variant			NM_001351661.2	ENSP00000507484	P2	A1Z1Q3-1

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2725

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00473

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0277

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0180

AC:

4520

AN:

250898

Hom.:

AF XY:

0.0174

AC XY:

2363

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.00351

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0274

Gnomad NFE exome

AF:

0.0307

Gnomad OTH exome

AF:

0.0164

GnomAD4 exome

AF:

0.0241

AC:

35243

AN:

1461686

Hom.:

541

Cov.:

AF XY:

0.0232

AC XY:

16862

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00377

Gnomad4 AMR exome

AF:

0.00767

Gnomad4 ASJ exome

AF:

0.00352

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.0272

Gnomad4 NFE exome

AF:

0.0288

Gnomad4 OTH exome

AF:

0.0187

GnomAD4 genome

AF:

0.0179

AC:

2724

AN:

152276

Hom.:

Cov.:

AF XY:

0.0174

AC XY:

1299

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00472

Gnomad4 AMR

AF:

0.0164

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0271

Gnomad4 NFE

AF:

0.0277

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0244

Hom.:

Bravo

AF:

0.0168

TwinsUK

AF:

0.0270

AC:

100

ALSPAC

AF:

0.0309

AC:

119

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0284

AC:

244

ExAC

AF:

0.0202

AC:

2451

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0223

EpiControl

AF:

0.0231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2021	This variant is associated with the following publications: (PMID: 29767709) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	FLRT3: BP4, BS1, BS2; MACROD2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

T;T

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

.;D

MetaRNN

Benign

0.0044

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.89

N;N

REVEL

Benign

0.070

Sift

Benign

0.033

D;D

Sift4G

Uncertain

0.033

D;D

Polyphen

0.0060

B;B

Vest4

0.087

MutPred

0.25

Loss of disorder (P = 0.1062);Loss of disorder (P = 0.1062);

MPC

0.98

ClinPred

0.020

GERP RS

6.1

Varity_R

0.14

gMVP

0.69

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