20-14326378-C-T

Variant names:

• chr20-14326378-C-T
• rs8120693
• NM_198391.3:c.1129G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• 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:5
• Conservation: PhyloP100: 3.25
• Publications: 9 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2289 AD,Unknown gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLRT3	NM_198391.3	MANE Select	c.1129G>A	p.Ala377Thr	missense	Exon 3 of 3	NP_938205.1
	MACROD2	NM_001351661.2	MANE Select	c.272-167101C>T		intron	N/A	NP_001338590.1
	FLRT3	NM_013281.4		c.1129G>A	p.Ala377Thr	missense	Exon 2 of 2	NP_037413.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLRT3	ENST00000341420.5	TSL:2 MANE Select	c.1129G>A	p.Ala377Thr	missense	Exon 3 of 3	ENSP00000339912.4
	FLRT3	ENST00000378053.3	TSL:1	c.1129G>A	p.Ala377Thr	missense	Exon 2 of 2	ENSP00000367292.3
	MACROD2	ENST00000684519.1	MANE Select	c.272-167101C>T		intron	N/A	ENSP00000507484.1

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

GnomAD2 exomes AF: 0.0110 AC: 2766 AN: 250884 AF XY: 0.0102

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 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

African (AFR) AF: 0.0266 AC: 890 AN: 33462

American (AMR) AF: 0.00573 AC: 256 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 94 AN: 26120

East Asian (EAS) AF: 0.00673 AC: 267 AN: 39694

South Asian (SAS) AF: 0.0116 AC: 1004 AN: 86258

European-Finnish (FIN) AF: 0.00998 AC: 533 AN: 53420

Middle Eastern (MID) AF: 0.0130 AC: 75 AN: 5760

European-Non Finnish (NFE) AF: 0.0115 AC: 12771 AN: 1111878

Other (OTH) AF: 0.0110 AC: 665 AN: 60382

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

African (AFR) AF: 0.0269 AC: 1118 AN: 41552

American (AMR) AF: 0.00747 AC: 114 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00909 AC: 47 AN: 5170

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4826

European-Finnish (FIN) AF: 0.00970 AC: 103 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0109 AC: 744 AN: 68000

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.0117 Hom.: 24

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29767709)

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLRT3: BP4, BS1, BS2; MACROD2: BS1, BS2

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.23
Sift	Benign	0.57	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.38
ClinPred		0.026	T
GERP RS		6.1
Varity_R		0.072
gMVP		0.47
Mutation Taster		=76/24	polymorphism (auto)

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: rs8120693; hg19: chr20-14307024;