Genetic Variant NM_001080432.3:c.1365-39703G>A (chr16-54072059-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.1365-39703G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0992 in 152,132 control chromosomes in the GnomAD database, including 1,246 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 0.099 ( 1246 hom., cov: 32)

Exomes 𝑓: 0.13 ( 0 hom. )

Consequence

FTO
NM_001080432.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0430

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:

LOC105371271 (HGNC:):

LOC105371271 links:

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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=-0.73).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTO	NM_001080432.3 link	c.1365-39703G>A		intron_variant	Intron 8 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.1365-39703G>A		intron_variant	Intron 8 of 8	1	NM_001080432.3	ENSP00000418823.1		Q9C0B1-1

Frequencies

GnomAD3 genomes

AF:

0.0991

AC:

15060

AN:

152006

Hom.:

1238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0586

Gnomad ASJ

AF:

0.0308

Gnomad EAS

AF:

0.141

Gnomad SAS

AF:

0.0894

Gnomad FIN

AF:

0.0609

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0433

Gnomad OTH

AF:

0.0804

GnomAD4 exome

AF:

0.125

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.167

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0992

AC:

15097

AN:

152124

Hom.:

1246

Cov.:

AF XY:

0.100

AC XY:

7435

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.221

AC:

9150

AN:

41462

American (AMR)

AF:

0.0585

AC:

894

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0308

AC:

107

AN:

3470

East Asian (EAS)

AF:

0.141

AC:

731

AN:

5172

South Asian (SAS)

AF:

0.0899

AC:

432

AN:

4806

European-Finnish (FIN)

AF:

0.0609

AC:

646

AN:

10604

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0433

AC:

2948

AN:

68006

Other (OTH)

AF:

0.0795

AC:

168

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

643

1286

1928

2571

3214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<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:

0.0512

Hom.:

171

Bravo

AF:

0.103

Asia WGS

AF:

0.101

AC:

351

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.2

(source)

DANN

Benign

0.75

PhyloP100

-0.043

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

Computational scores

Splicing

Publications

Other links and lift over