dbSNP rs726344: FNDC5:c.499+250C>T (chr1-32867503-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153756.3(FNDC5):c.499+250C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,208 control chromosomes in the GnomAD database, including 2,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2372 hom., cov: 32)

Consequence

FNDC5
NM_153756.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.895

Publications

25 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 1-32867503-G-A is Benign according to our data. Variant chr1-32867503-G-A is described in ClinVar as Benign. ClinVar VariationId is 1236585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNDC5	NM_153756.3 link	c.499+250C>T		intron_variant	Intron 4 of 5	ENST00000373471.9	NP_715637.2	Q8NAU1-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
FNDC5	ENST00000373471.9 link	c.499+250C>T	intron_variant	Intron 4 of 5	2	NM_153756.3	ENSP00000362570.5	Q8NAU1-1A0A0A0MRR6
FNDC5	ENST00000496770.1 link	c.274+250C>T	intron_variant	Intron 4 of 4	1		ENSP00000476320.1	Q8NAU1-3
FNDC5	ENST00000710568.1 link	c.643+250C>T	intron_variant	Intron 4 of 5			ENSP00000518350.1
FNDC5	ENST00000649537.2 link	c.466+250C>T	intron_variant	Intron 4 of 5			ENSP00000497837.2	A0A3B3ITP1

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23945

AN:

152090

Hom.:

2364

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.200

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0628

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.137

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.158

AC:

23999

AN:

152208

Hom.:

2372

Cov.:

AF XY:

0.157

AC XY:

11715

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.268

AC:

11108

AN:

41510

American (AMR)

AF:

0.200

AC:

3054

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

347

AN:

3466

East Asian (EAS)

AF:

0.00174

AC:

AN:

5186

South Asian (SAS)

AF:

0.0627

AC:

302

AN:

4820

European-Finnish (FIN)

AF:

0.126

AC:

1338

AN:

10612

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.110

AC:

7450

AN:

68008

Other (OTH)

AF:

0.136

AC:

288

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

989

1977

2966

3954

4943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0926

Hom.:

166

Bravo

AF:

0.165

Asia WGS

AF:

0.0590

AC:

207

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25427998) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

9.1

(source)

DANN

Benign

0.67

PhyloP100

0.90

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over