Genetic Variant NM_001080432.3:c.46-27777C>A (chr16-53782363-C-A) – 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.46-27777C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 152,066 control chromosomes in the GnomAD database, including 12,270 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 0.40 ( 12270 hom., cov: 32)

Consequence

FTO
NM_001080432.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.716

Publications

754 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), Orphanet, G2P, PanelApp Australia

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=-0.82).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.432 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.46-27777C>A	intron	N/A	NP_001073901.1	Q9C0B1-1
FTO	NM_001363894.2		c.46-27777C>A	intron	N/A	NP_001350823.1
FTO	NM_001363891.2		c.46-27777C>A	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.46-27777C>A	intron	N/A	ENSP00000418823.1	Q9C0B1-1
FTO	ENST00000637969.1	TSL:5	c.46-27777C>A	intron	N/A	ENSP00000490516.1	A0A1B0GVH5
FTO	ENST00000918264.1		c.46-27777C>A	intron	N/A	ENSP00000588323.1

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60202

AN:

151948

Hom.:

12261

Cov.:

show subpopulations

Gnomad AFR

AF:

0.438

Gnomad AMI

AF:

0.464

Gnomad AMR

AF:

0.311

Gnomad ASJ

AF:

0.505

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.315

Gnomad FIN

AF:

0.399

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.408

Gnomad OTH

AF:

0.390

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

GnomAD4 genome

AF:

0.396

AC:

60234

AN:

152066

Hom.:

12270

Cov.:

AF XY:

0.392

AC XY:

29148

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.437

AC:

18132

AN:

41452

American (AMR)

AF:

0.310

AC:

4743

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.505

AC:

1752

AN:

3472

East Asian (EAS)

AF:

0.152

AC:

785

AN:

5170

South Asian (SAS)

AF:

0.314

AC:

1514

AN:

4818

European-Finnish (FIN)

AF:

0.399

AC:

4224

AN:

10578

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.408

AC:

27724

AN:

67978

Other (OTH)

AF:

0.391

AC:

825

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1864

3729

5593

7458

9322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

568

1136

1704

2272

2840

<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:

0.395

Hom.:

58880

Bravo

AF:

0.387

Asia WGS

AF:

0.288

AC:

1002

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.0

(source)

DANN

Benign

0.62

PhyloP100

0.72

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