rs398124654

Variant names:

• chr20-14326491-T-C
• rs398124654
• NM_198391.3:c.1016A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198391.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLRT3	NM_198391.3	MANE Select	c.1016A>G	p.Lys339Arg	missense	Exon 3 of 3	NP_938205.1	Q9NZU0
	MACROD2	NM_001351661.2	MANE Select	c.272-166988T>C		intron	N/A	NP_001338590.1	A1Z1Q3-1
	FLRT3	NM_013281.4		c.1016A>G	p.Lys339Arg	missense	Exon 2 of 2	NP_037413.1	Q9NZU0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLRT3	ENST00000341420.5	TSL:2 MANE Select	c.1016A>G	p.Lys339Arg	missense	Exon 3 of 3	ENSP00000339912.4	Q9NZU0
	FLRT3	ENST00000378053.3	TSL:1	c.1016A>G	p.Lys339Arg	missense	Exon 2 of 2	ENSP00000367292.3	Q9NZU0
	MACROD2	ENST00000684519.1	MANE Select	c.272-166988T>C		intron	N/A	ENSP00000507484.1	A1Z1Q3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hypogonadotropic hypogonadism 21 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.17	N
PhyloP100		5.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.075
Sift	Benign	0.47	T
Sift4G	Benign	0.51	T
Polyphen		0.0010	B
Vest4		0.25
MutPred		0.38		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
Mutation Taster		=40/60	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398124654; hg19: chr20-14307137;