Genetic Variant FTO:p.Lys20Lys (chr16-53911439-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The ENST00000463855.1(FTO):c.60G>A(p.Lys20Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 703,074 control chromosomes in the GnomAD database, including 3,228 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.029 ( 383 hom., cov: 32)

Exomes 𝑓: 0.045 ( 2845 hom. )

Consequence

FTO
ENST00000463855.1 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.767

Publications

9 publications found

Variant links:

Genes affected

FTO (HGNC:24678): (FTO alpha-ketoglutarate dependent dioxygenase) This gene is a nuclear protein of the AlkB related non-haem iron and 2-oxoglutarate-dependent oxygenase superfamily but the exact physiological function of this gene is not known. Other non-heme iron enzymes function to reverse alkylated DNA and RNA damage by oxidative demethylation. Studies in mice and humans indicate a role in nervous and cardiovascular systems and a strong association with body mass index, obesity risk, and type 2 diabetes. [provided by RefSeq, Jul 2011]

FTO Gene-Disease associations (from GenCC):

lethal polymalformative syndrome, Boissel type
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

FTO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP7

Synonymous conserved (PhyloP=-0.767 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTO	NM_001080432.3 link	c.1239+22488G>A		intron_variant	Intron 7 of 8	ENST00000471389.6	NP_001073901.1	Q9C0B1-1B3KU60Q99770

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTO	ENST00000471389.6 link	c.1239+22488G>A		intron_variant	Intron 7 of 8	1	NM_001080432.3	ENSP00000418823.1		Q9C0B1-1

Frequencies

GnomAD3 genomes

AF:

0.0286

AC:

4352

AN:

152174

Hom.:

375

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00454

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.104

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.313

Gnomad SAS

AF:

0.0795

Gnomad FIN

AF:

0.0299

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00250

Gnomad OTH

AF:

0.0339

GnomAD2 exomes

AF:

0.0743

AC:

10205

AN:

137312

AF XY:

0.0679

show subpopulations

Gnomad AFR exome

AF:

0.00386

Gnomad AMR exome

AF:

0.196

Gnomad ASJ exome

AF:

0.000962

Gnomad EAS exome

AF:

0.321

Gnomad FIN exome

AF:

0.0269

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.0435

GnomAD4 exome

AF:

0.0450

AC:

24782

AN:

550780

Hom.:

2845

Cov.:

AF XY:

0.0444

AC XY:

13249

AN XY:

298148

show subpopulations

African (AFR)

AF:

0.00386

AC:

AN:

15808

American (AMR)

AF:

0.186

AC:

6452

AN:

34714

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

20030

East Asian (EAS)

AF:

0.342

AC:

10966

AN:

32098

South Asian (SAS)

AF:

0.0665

AC:

4175

AN:

62752

European-Finnish (FIN)

AF:

0.0281

AC:

948

AN:

33706

Middle Eastern (MID)

AF:

0.00442

AC:

AN:

4076

European-Non Finnish (NFE)

AF:

0.00300

AC:

951

AN:

316980

Other (OTH)

AF:

0.0384

AC:

1175

AN:

30616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

1099

2198

3298

4397

5496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0287

AC:

4364

AN:

152294

Hom.:

383

Cov.:

AF XY:

0.0331

AC XY:

2463

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00452

AC:

188

AN:

41558

American (AMR)

AF:

0.105

AC:

1611

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.312

AC:

1616

AN:

5172

South Asian (SAS)

AF:

0.0790

AC:

381

AN:

4824

European-Finnish (FIN)

AF:

0.0299

AC:

317

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00250

AC:

170

AN:

68034

Other (OTH)

AF:

0.0350

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

186

372

559

745

931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0221

Hom.:

174

Bravo

AF:

0.0375

Asia WGS

AF:

0.178

AC:

620

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.040

(source)

DANN

Benign

0.31

PhyloP100

-0.77

PromoterAI

-0.0044

Neutral

(source)

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over