20-14326307-G-T

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.1200C>A(p.His400Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,613,598 control chromosomes in the GnomAD database, including 168,244 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.38 (12660 hom., cov: 32)
  • Exomes 𝑓: 0.45 (155584 hom.)
• Consequence: FLRT3 NM_198391.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.41

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=1.1417994E-4).
• BP6: Variant 20-14326307-G-T is Benign according to our data. Variant chr20-14326307-G-T is described in ClinVar as [Benign]. Clinvar id is 1288590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLRT3	NM_198391.3	c.1200C>A	p.His400Gln	missense_variant	3/3	ENST00000341420.5
MACROD2	NM_001351661.2	c.272-167172G>T		intron_variant		ENST00000684519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLRT3	ENST00000341420.5	c.1200C>A	p.His400Gln	missense_variant	3/3	2	NM_198391.3	P1
MACROD2	ENST00000684519.1	c.272-167172G>T		intron_variant			NM_001351661.2	P2

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58351 AN: 151880 Hom.: 12657 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.383

GnomAD3 exomes AF: 0.410 AC: 102680 AN: 250474 Hom.: 23008 AF XY: 0.408 AC XY: 55161 AN XY: 135348

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.450

Gnomad EAS exome AF: 0.168

Gnomad SAS exome AF: 0.249

Gnomad FIN exome AF: 0.543

Gnomad NFE exome AF: 0.488

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.452 AC: 660700 AN: 1461600 Hom.: 155584 Cov.: 63 AF XY: 0.446 AC XY: 324538 AN XY: 727100

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.423

Gnomad4 ASJ exome AF: 0.449

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.546

Gnomad4 NFE exome AF: 0.485

Gnomad4 OTH exome AF: 0.420

GnomAD4 genome AF: 0.384 AC: 58378 AN: 151998 Hom.: 12660 Cov.: 32 AF XY: 0.384 AC XY: 28535 AN XY: 74274

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.463

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.540

Gnomad4 NFE AF: 0.489

Gnomad4 OTH AF: 0.380

Alfa AF: 0.451 Hom.: 37839

Bravo AF: 0.368

TwinsUK AF: 0.488 AC: 1809

ALSPAC AF: 0.492 AC: 1898

ESP6500AA AF: 0.212 AC: 932

ESP6500EA AF: 0.482 AC: 4141

ExAC AF: 0.406 AC: 49305

Asia WGS AF: 0.238 AC: 829 AN: 3478

EpiCase AF: 0.463

EpiControl AF: 0.461

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 31, 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	0.074
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	13
Dann	Benign	0.85
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.00011	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	2.4e-11	P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.11
Sift	Benign	0.34	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0	B;B
Vest4		0.013
MutPred		0.081		Gain of methylation at K395 (P = 0.1362);Gain of methylation at K395 (P = 0.1362);
MPC		0.39
ClinPred		0.015	T
GERP RS		1.6
Varity_R		0.060
gMVP		0.47

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: rs6079391; hg19: chr20-14306953; COSMIC: COSV53949211; COSMIC: COSV53949211;