Genetic Variant FTO:c.*3705G>A (chr16-54115620-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001080432.3(FTO):c.*3705G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 151,962 control chromosomes in the GnomAD database, including 1,999 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 0.15 ( 1998 hom., cov: 31)

Exomes 𝑓: 0.11 ( 1 hom. )

Consequence

FTO
NM_001080432.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.590

Publications

11 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTO	NM_001080432.3	MANE Select	c.*3705G>A		3_prime_UTR	Exon 9 of 9	NP_001073901.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FTO	ENST00000471389.6	TSL:1 MANE Select	c.*3705G>A	3_prime_UTR	Exon 9 of 9	ENSP00000418823.1
FTO	ENST00000637969.1	TSL:5	c.1492+3731G>A	intron	N/A	ENSP00000490516.1
FTO	ENST00000612285.2	TSL:5	c.517+3731G>A	intron	N/A	ENSP00000490300.1

Frequencies

GnomAD3 genomes

AF:

0.148

AC:

22505

AN:

151602

Hom.:

1991

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0571

Gnomad AMI

AF:

0.185

Gnomad AMR

AF:

0.197

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.290

Gnomad SAS

AF:

0.248

Gnomad FIN

AF:

0.169

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.169

Gnomad OTH

AF:

0.171

GnomAD4 exome

AF:

0.108

AC:

AN:

240

Hom.:

Cov.:

AF XY:

0.112

AC XY:

AN XY:

170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.167

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.121

AC:

AN:

198

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.148

AC:

22520

AN:

151722

Hom.:

1998

Cov.:

AF XY:

0.151

AC XY:

11185

AN XY:

74124

show subpopulations

African (AFR)

AF:

0.0569

AC:

2358

AN:

41418

American (AMR)

AF:

0.198

AC:

3017

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

659

AN:

3460

East Asian (EAS)

AF:

0.290

AC:

1463

AN:

5044

South Asian (SAS)

AF:

0.248

AC:

1185

AN:

4782

European-Finnish (FIN)

AF:

0.169

AC:

1788

AN:

10554

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.169

AC:

11454

AN:

67892

Other (OTH)

AF:

0.175

AC:

369

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

907

1814

2722

3629

4536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

260

520

780

1040

1300

<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:

0.166

Hom.:

2419

Bravo

AF:

0.147

Asia WGS

AF:

0.267

AC:

926

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.47

(source)

DANN

Benign

0.80

PhyloP100

-0.59

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over