20-14326127-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198391.3(FLRT3):c.1380A>C(p.Glu460Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0298 in 1,613,846 control chromosomes in the GnomAD database, including 1,115 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.052 (328 hom., cov: 32)
  • Exomes 𝑓: 0.027 (787 hom.)
• Consequence: FLRT3 NM_198391.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.162

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017079115).
• BP6: Variant 20-14326127-T-G is Benign according to our data. Variant chr20-14326127-T-G is described in ClinVar as [Benign]. Clinvar id is 1259515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLRT3	NM_198391.3	c.1380A>C	p.Glu460Asp	missense_variant	3/3	ENST00000341420.5
MACROD2	NM_001351661.2	c.272-167352T>G		intron_variant		ENST00000684519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLRT3	ENST00000341420.5	c.1380A>C	p.Glu460Asp	missense_variant	3/3	2	NM_198391.3	P1
MACROD2	ENST00000684519.1	c.272-167352T>G		intron_variant			NM_001351661.2	P2

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7904 AN: 152120 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0283

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0498

GnomAD3 exomes AF: 0.0293 AC: 7338 AN: 250630 Hom.: 222 AF XY: 0.0272 AC XY: 3687 AN XY: 135444

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0325

Gnomad EAS exome AF: 0.0318

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.0290

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0275 AC: 40122 AN: 1461608 Hom.: 787 Cov.: 30 AF XY: 0.0270 AC XY: 19598 AN XY: 727110

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.0152

Gnomad4 ASJ exome AF: 0.0327

Gnomad4 EAS exome AF: 0.0202

Gnomad4 SAS exome AF: 0.0162

Gnomad4 FIN exome AF: 0.0304

Gnomad4 NFE exome AF: 0.0256

Gnomad4 OTH exome AF: 0.0336

GnomAD4 genome AF: 0.0520 AC: 7919 AN: 152238 Hom.: 328 Cov.: 32 AF XY: 0.0503 AC XY: 3745 AN XY: 74436

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.0236

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.0280

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.0281

Gnomad4 NFE AF: 0.0260

Gnomad4 OTH AF: 0.0492

Alfa AF: 0.0306 Hom.: 180

Bravo AF: 0.0542

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.120 AC: 527

ESP6500EA AF: 0.0248 AC: 213

ExAC AF: 0.0315 AC: 3820

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0286

EpiControl AF: 0.0246

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	8.9
Dann	Benign	0.81
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.76	D
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.76	N;N
MutationTaster	Benign	3.0e-14	P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.48	N;N
REVEL	Benign	0.069
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.035
MutPred		0.25		Gain of catalytic residue at G459 (P = 0.0789);Gain of catalytic residue at G459 (P = 0.0789);
MPC		0.36
ClinPred		0.0021	T
GERP RS		2.6
Varity_R		0.050
gMVP		0.53

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: rs35253731; hg19: chr20-14306773;