rs1861866

Variant names:

• chr16-53770428-C-T
• rs1861866
• NM_001080432.3:c.46-39712C>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.46-39712C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 151,976 control chromosomes in the GnomAD database, including 25,816 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 0.57 (25816 hom., cov: 32)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447
• Publications: 20 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTO	NM_001080432.3	c.46-39712C>T		intron_variant	Intron 1 of 8	ENST00000471389.6	NP_001073901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTO	ENST00000471389.6	c.46-39712C>T		intron_variant	Intron 1 of 8	1	NM_001080432.3	ENSP00000418823.1

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87190 AN: 151858 Hom.: 25781 Cov.: 32

Gnomad AFR AF: 0.720

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.566

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

GnomAD4 genome AF: 0.574 AC: 87272 AN: 151976 Hom.: 25816 Cov.: 32 AF XY: 0.572 AC XY: 42462 AN XY: 74290

African (AFR) AF: 0.721 AC: 29881 AN: 41470

American (AMR) AF: 0.479 AC: 7297 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2109 AN: 3470

East Asian (EAS) AF: 0.646 AC: 3324 AN: 5148

South Asian (SAS) AF: 0.493 AC: 2374 AN: 4820

European-Finnish (FIN) AF: 0.512 AC: 5406 AN: 10552

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.516 AC: 35094 AN: 67950

Other (OTH) AF: 0.565 AC: 1194 AN: 2112

Alfa AF: 0.593 Hom.: 9014

Bravo AF: 0.576

Asia WGS AF: 0.593 AC: 2058 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.82
DANN	Benign	0.40
PhyloP100		-0.45
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: rs1861866; hg19: chr16-53804340; COSMIC: COSV67113889;