Variant 1-32867800-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153756.3(FNDC5):c.452G>A(p.Arg151Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

FNDC5
NM_153756.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.01

Variant links:

Genes affected

FNDC5 (HGNC:20240): (fibronectin type III domain containing 5) This gene encodes a secreted protein that is released from muscle cells during exercise. The encoded protein may participate in the development of brown fat. Translation of the precursor protein initiates at a non-AUG start codon at a position that is conserved as an AUG start codon in other organisms. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

FNDC5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.074347675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FNDC5	NM_153756.3 linkuse as main transcript	c.452G>A	p.Arg151Gln	missense_variant	4/6	ENST00000373471.9	NP_715637.2
FNDC5	NM_001171940.2 linkuse as main transcript	c.452G>A	p.Arg151Gln	missense_variant	4/6		NP_001165411.2
FNDC5	NM_001171941.3 linkuse as main transcript	c.227G>A	p.Arg76Gln	missense_variant	4/5		NP_001165412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FNDC5	ENST00000373471.9 linkuse as main transcript	c.452G>A	p.Arg151Gln	missense_variant	4/6	2	NM_153756.3	ENSP00000362570		Q8NAU1-1
FNDC5	ENST00000496770.1 linkuse as main transcript	c.227G>A	p.Arg76Gln	missense_variant	4/5	1		ENSP00000476320		Q8NAU1-3
FNDC5	ENST00000710568.1 linkuse as main transcript	c.596G>A	p.Arg199Gln	missense_variant	4/6			ENSP00000518350	P1
FNDC5	ENST00000649537.2 linkuse as main transcript	c.419G>A	p.Arg140Gln	missense_variant	4/6			ENSP00000497837

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000338

AC:

AN:

251410

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000376

AC:

550

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

253

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000428

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000467

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.000539

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000340

Hom.:

Bravo

AF:

0.000348

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000296

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.227G>A (p.R76Q) alteration is located in exon 4 (coding exon 2) of the FNDC5 gene. This alteration results from a G to A substitution at nucleotide position 227, causing the arginine (R) at amino acid position 76 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0089

T;.;T;.

Eigen

Benign

0.0012

Eigen_PC

Benign

0.096

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Benign

0.0050

MetaRNN

Benign

0.074

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.64

.;.;N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

REVEL

Benign

0.11

Sift4G

Benign

1.0

T;.;.;T

Polyphen

0.61

.;.;.;P

Vest4

0.44

MVP

0.52

ClinPred

0.21

GERP RS

4.1

Varity_R

0.25

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over