chr20-14327076-C-A

Variant names:

• chr20-14327076-C-A
• rs398124652
• NM_198391.3:c.431G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198391.3(FLRT3):​c.431G>T​(p.Ser144Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLRT3 NM_198391.3 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 7.91
• Publications: 1 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLRT3	NM_198391.3	c.431G>T	p.Ser144Ile	missense_variant	Exon 3 of 3	ENST00000341420.5	NP_938205.1
MACROD2	NM_001351661.2	c.272-166403C>A		intron_variant	Intron 3 of 17	ENST00000684519.1	NP_001338590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLRT3	ENST00000341420.5	c.431G>T	p.Ser144Ile	missense_variant	Exon 3 of 3	2	NM_198391.3	ENSP00000339912.4
MACROD2	ENST00000684519.1	c.272-166403C>A		intron_variant	Intron 3 of 17		NM_001351661.2	ENSP00000507484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

HYPOGONADOTROPIC HYPOGONADISM 21 WITH ANOSMIA, SUSCEPTIBILITY TO Other:1

May 02, 2013

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.56	N;N
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.020	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.48		Loss of disorder (P = 0.0083);Loss of disorder (P = 0.0083);
MVP		0.54
MPC		1.3
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.70
gMVP		0.58
Mutation Taster		=5/95	disease causing

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: rs398124652; hg19: chr20-14307722; COSMIC: COSV108042847; COSMIC: COSV108042847;