Genetic Variant FTO:c.46-13587A>G (chr16-53796553-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is . The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001080432.3(FTO):c.46-13587A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 152,122 control chromosomes in the GnomAD database, including 10,559 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 0.36 ( 10559 hom., cov: 32)

Consequence

FTO
NM_001080432.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.434

Publications

252 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: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

FTO links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001080432.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080432.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FTO	NM_001080432.3	MANE Select	c.46-13587A>G	intron	N/A	NP_001073901.1	Q9C0B1-1
FTO	NM_001363894.2		c.46-13587A>G	intron	N/A	NP_001350823.1
FTO	NM_001363891.2		c.46-13587A>G	intron	N/A	NP_001350820.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FTO	ENST00000471389.6	TSL:1 MANE Select	c.46-13587A>G	intron	N/A	ENSP00000418823.1	Q9C0B1-1
FTO	ENST00000637969.1	TSL:5	c.46-13587A>G	intron	N/A	ENSP00000490516.1	A0A1B0GVH5
FTO	ENST00000918264.1		c.46-13587A>G	intron	N/A	ENSP00000588323.1

Frequencies

GnomAD3 genomes

AF:

0.356

AC:

54178

AN:

152004

Hom.:

10559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.205

Gnomad AMI

AF:

0.464

Gnomad AMR

AF:

0.318

Gnomad ASJ

AF:

0.538

Gnomad EAS

AF:

0.204

Gnomad SAS

AF:

0.425

Gnomad FIN

AF:

0.415

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.444

Gnomad OTH

AF:

0.366

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

GnomAD4 genome

AF:

0.356

AC:

54193

AN:

152122

Hom.:

10559

Cov.:

AF XY:

0.354

AC XY:

26351

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.205

AC:

8497

AN:

41534

American (AMR)

AF:

0.319

AC:

4871

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.538

AC:

1866

AN:

3468

East Asian (EAS)

AF:

0.204

AC:

1056

AN:

5170

South Asian (SAS)

AF:

0.424

AC:

2045

AN:

4822

European-Finnish (FIN)

AF:

0.415

AC:

4391

AN:

10568

Middle Eastern (MID)

AF:

0.367

AC:

108

AN:

294

European-Non Finnish (NFE)

AF:

0.444

AC:

30160

AN:

67950

Other (OTH)

AF:

0.367

AC:

776

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1700

3400

5100

6800

8500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.406

Hom.:

41978

Bravo

AF:

0.338

Asia WGS

AF:

0.332

AC:

1154

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.94

(source)

DANN

Benign

0.49

PhyloP100

-0.43

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over