20-14326378-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198391.3(FLRT3):c.1129G>A(p.Ala377Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,613,912 control chromosomes in the GnomAD database, including 142 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., cov: 32)
  • Exomes 𝑓: 0.011 (118 hom.)
• Consequence: FLRT3 NM_198391.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.25

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=0.0016800463).
• BP6: Variant 20-14326378-C-T is Benign according to our data. Variant chr20-14326378-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.015 (2289/152224) while in subpopulation AFR AF= 0.0269 (1118/41552). AF 95% confidence interval is 0.0256. There are 24 homozygotes in gnomad4. There are 1106 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2290 AD,Digenic,Multigenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLRT3	NM_198391.3	c.1129G>A	p.Ala377Thr	missense_variant	3/3	ENST00000341420.5
MACROD2	NM_001351661.2	c.272-167101C>T		intron_variant		ENST00000684519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLRT3	ENST00000341420.5	c.1129G>A	p.Ala377Thr	missense_variant	3/3	2	NM_198391.3	P1
MACROD2	ENST00000684519.1	c.272-167101C>T		intron_variant			NM_001351661.2	P2

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2290 AN: 152106 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.00754

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00907

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00970

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0110 AC: 2766 AN: 250884 Hom.: 37 AF XY: 0.0102 AC XY: 1377 AN XY: 135562

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00974

Gnomad SAS exome AF: 0.0114

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0113 AC: 16555 AN: 1461688 Hom.: 118 Cov.: 35 AF XY: 0.0111 AC XY: 8090 AN XY: 727144

Gnomad4 AFR exome AF: 0.0266

Gnomad4 AMR exome AF: 0.00573

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.00673

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.00998

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.0150 AC: 2289 AN: 152224 Hom.: 24 Cov.: 32 AF XY: 0.0149 AC XY: 1106 AN XY: 74416

Gnomad4 AFR AF: 0.0269

Gnomad4 AMR AF: 0.00747

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00909

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.00970

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0108 Hom.: 18

Bravo AF: 0.0151

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.0114 AC: 1388

Asia WGS AF: 0.0150 AC: 52 AN: 3476

EpiCase AF: 0.0107

EpiControl AF: 0.00960

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	FLRT3: BP4, BS1, BS2; MACROD2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	This variant is associated with the following publications: (PMID: 29767709) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	17
Dann	Benign	0.88
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.23
Sift	Benign	0.57	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.030
MPC		0.38
ClinPred		0.026	T
GERP RS		6.1
Varity_R		0.072
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: rs8120693; hg19: chr20-14307024;