16-53963390-C-T

Variant names:

• chr16-53963390-C-T
• rs12446047
• NM_001080432.3:c.1364+29281C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001080432.3(FTO):​c.1364+29281C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 151,960 control chromosomes in the GnomAD database, including 16,488 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 0.46 (16488 hom., cov: 32)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.135
• Publications: 11 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTO	NM_001080432.3	c.1364+29281C>T		intron_variant	Intron 8 of 8	ENST00000471389.6	NP_001073901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTO	ENST00000471389.6	c.1364+29281C>T		intron_variant	Intron 8 of 8	1	NM_001080432.3	ENSP00000418823.1

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69138 AN: 151842 Hom.: 16496 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.738

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.503

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

GnomAD4 genome AF: 0.455 AC: 69147 AN: 151960 Hom.: 16488 Cov.: 32 AF XY: 0.452 AC XY: 33548 AN XY: 74266

African (AFR) AF: 0.330 AC: 13676 AN: 41446

American (AMR) AF: 0.535 AC: 8174 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1668 AN: 3468

East Asian (EAS) AF: 0.738 AC: 3803 AN: 5156

South Asian (SAS) AF: 0.426 AC: 2052 AN: 4812

European-Finnish (FIN) AF: 0.376 AC: 3968 AN: 10540

Middle Eastern (MID) AF: 0.531 AC: 154 AN: 290

European-Non Finnish (NFE) AF: 0.500 AC: 34006 AN: 67952

Other (OTH) AF: 0.501 AC: 1058 AN: 2112

Alfa AF: 0.479 Hom.: 9606

Bravo AF: 0.466

Asia WGS AF: 0.529 AC: 1838 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.32
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12446047; hg19: chr16-53997302;