rs9921255

Variant names:

• chr16-53975416-T-C
• rs9921255
• NM_001080432.3:c.1364+41307T>C

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+41307T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 152,048 control chromosomes in the GnomAD database, including 3,063 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 0.20 (3063 hom., cov: 32)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.721
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.214 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.1364+41307T>C		intron	N/A	NP_001073901.1
	FTO	NM_001363894.2		c.1427+41307T>C		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.1394+41307T>C		intron	N/A	NP_001350820.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTO	ENST00000471389.6	TSL:1 MANE Select	c.1364+41307T>C		intron	N/A	ENSP00000418823.1
	FTO	ENST00000268349.7	TSL:1	c.81-9522T>C		intron	N/A	ENSP00000268349.7
	FTO	ENST00000463855.1	TSL:1	c.230+41307T>C		intron	N/A	ENSP00000417843.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29829 AN: 151930 Hom.: 3056 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.191

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

GnomAD4 genome AF: 0.196 AC: 29864 AN: 152048 Hom.: 3063 Cov.: 32 AF XY: 0.194 AC XY: 14405 AN XY: 74320

African (AFR) AF: 0.205 AC: 8488 AN: 41482

American (AMR) AF: 0.220 AC: 3366 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 538 AN: 3466

East Asian (EAS) AF: 0.120 AC: 623 AN: 5180

South Asian (SAS) AF: 0.123 AC: 590 AN: 4812

European-Finnish (FIN) AF: 0.189 AC: 1993 AN: 10562

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13644 AN: 67962

Other (OTH) AF: 0.189 AC: 399 AN: 2110

Alfa AF: 0.200 Hom.: 3958

Bravo AF: 0.204

Asia WGS AF: 0.126 AC: 441 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.58
PhyloP100		-0.72
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: rs9921255; hg19: chr16-54009328;