rs398124654

Positions:

• chr20-14326491-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_198391.3(FLRT3):​c.1016A>G​(p.Lys339Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLRT3 NM_198391.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.15

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]

MACROD2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-14326491-T-C is Pathogenic according to our data. Variant chr20-14326491-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 50865.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11818424). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FLRT3	NM_198391.3	c.1016A>G	p.Lys339Arg	missense_variant	3/3	ENST00000341420.5	NP_938205.1
MACROD2	NM_001351661.2	c.272-166988T>C		intron_variant		ENST00000684519.1	NP_001338590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FLRT3	ENST00000341420.5	c.1016A>G	p.Lys339Arg	missense_variant	3/3	2	NM_198391.3	ENSP00000339912.4
MACROD2	ENST00000684519.1	c.272-166988T>C		intron_variant			NM_001351661.2	ENSP00000507484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypogonadotropic hypogonadism 21 with or without anosmia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 02, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.040	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.86	.;D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.17	N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.10	N;N
REVEL	Benign	0.075
Sift	Benign	0.47	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0010	B;B
Vest4		0.25
MutPred		0.38		Loss of ubiquitination at K339 (P = 0.0255);Loss of ubiquitination at K339 (P = 0.0255);
MVP		0.16
MPC		0.33
ClinPred		0.64	D
GERP RS		6.1
Varity_R		0.38
gMVP		0.49

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: rs398124654; hg19: chr20-14307137;