chr20-14326395-G-A

Position:

• chr20-14326395-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198391.3(FLRT3):​c.1112C>T​(p.Pro371Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: FLRT3 NM_198391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92

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]

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]

ACMG classification

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=0.17687428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLRT3	NM_198391.3	c.1112C>T	p.Pro371Leu	missense_variant	3/3	ENST00000341420.5
MACROD2	NM_001351661.2	c.272-167084G>A		intron_variant		ENST00000684519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLRT3	ENST00000341420.5	c.1112C>T	p.Pro371Leu	missense_variant	3/3	2	NM_198391.3	P1
MACROD2	ENST00000684519.1	c.272-167084G>A		intron_variant			NM_001351661.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2022

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. This variant has not been reported in the literature in individuals affected with FLRT3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 371 of the FLRT3 protein (p.Pro371Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	0.066
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.10
Sift	Benign	0.098	T;T
Sift4G	Uncertain	0.060	T;T
Polyphen		0.0	B;B
Vest4		0.16
MutPred		0.48		Loss of glycosylation at T368 (P = 0.0344);Loss of glycosylation at T368 (P = 0.0344);
MVP		0.18
MPC		0.40
ClinPred		0.66	D
GERP RS		6.1
Varity_R		0.078
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-14307041;