20-14326373-T-G

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.1134A>C(p.Gln378His) variant causes a missense change. The variant allele was found at a frequency of 0.0235 in 1,613,962 control chromosomes in the GnomAD database, including 587 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (46 hom., cov: 32)
  • Exomes 𝑓: 0.024 (541 hom.)
• Consequence: FLRT3 NM_198391.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.97

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=0.004434198).
• BP6: Variant 20-14326373-T-G is Benign according to our data. Variant chr20-14326373-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1317710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-14326373-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2724/152276) while in subpopulation NFE AF= 0.0277 (1885/68020). AF 95% confidence interval is 0.0267. There are 46 homozygotes in gnomad4. There are 1299 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2725 AD,Digenic,Multigenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLRT3	NM_198391.3	c.1134A>C	p.Gln378His	missense_variant	3/3	ENST00000341420.5
MACROD2	NM_001351661.2	c.272-167106T>G		intron_variant		ENST00000684519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLRT3	ENST00000341420.5	c.1134A>C	p.Gln378His	missense_variant	3/3	2	NM_198391.3	P1
MACROD2	ENST00000684519.1	c.272-167106T>G		intron_variant			NM_001351661.2	P2

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2725 AN: 152158 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00473

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0180 AC: 4520 AN: 250898 Hom.: 75 AF XY: 0.0174 AC XY: 2363 AN XY: 135574

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0274

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0164

GnomAD4 exome AF: 0.0241 AC: 35243 AN: 1461686 Hom.: 541 Cov.: 35 AF XY: 0.0232 AC XY: 16862 AN XY: 727142

Gnomad4 AFR exome AF: 0.00377

Gnomad4 AMR exome AF: 0.00767

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.0272

Gnomad4 NFE exome AF: 0.0288

Gnomad4 OTH exome AF: 0.0187

GnomAD4 genome AF: 0.0179 AC: 2724 AN: 152276 Hom.: 46 Cov.: 32 AF XY: 0.0174 AC XY: 1299 AN XY: 74454

Gnomad4 AFR AF: 0.00472

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.0277

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0244 Hom.: 90

Bravo AF: 0.0168

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0284 AC: 244

ExAC AF: 0.0202 AC: 2451

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0223

EpiControl AF: 0.0231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2021	This variant is associated with the following publications: (PMID: 29767709) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	FLRT3: BP4, BS1, BS2; MACROD2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.068	T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.070
Sift	Benign	0.033	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		0.0060	B;B
Vest4		0.087
MutPred		0.25		Loss of disorder (P = 0.1062);Loss of disorder (P = 0.1062);
MPC		0.98
ClinPred		0.020	T
GERP RS		6.1
Varity_R		0.14
gMVP		0.69

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: rs36034779; hg19: chr20-14307019; COSMIC: COSV99037133; COSMIC: COSV99037133;