rs1421085

Variant names:

• chr16-53767042-T-C
• rs1421085
• NM_001080432.3:c.46-43098T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001363894.2(FTO):​c.46-43098T>C variant causes a intron change. The variant allele was found at a frequency of 0.308 in 152,026 control chromosomes in the GnomAD database, including 8,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: 𝑓 0.31 (8801 hom., cov: 32)
• Consequence: FTO NM_001363894.2 intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 4.50
• Publications: 665 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

LOC124903691 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363894.2. 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.46-43098T>C		intron	N/A	NP_001073901.1
	FTO	NM_001363894.2		c.46-43098T>C		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.46-43098T>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.46-43098T>C		intron	N/A	ENSP00000418823.1
	FTO	ENST00000637969.1	TSL:5	c.46-43098T>C		intron	N/A	ENSP00000490516.1
	FTO	ENST00000918264.1		c.46-43098T>C		intron	N/A	ENSP00000588323.1

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46878 AN: 151908 Hom.: 8806 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.337

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

GnomAD4 genome AF: 0.308 AC: 46862 AN: 152026 Hom.: 8801 Cov.: 32 AF XY: 0.309 AC XY: 22982 AN XY: 74308

African (AFR) AF: 0.102 AC: 4231 AN: 41482

American (AMR) AF: 0.289 AC: 4411 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1773 AN: 3470

East Asian (EAS) AF: 0.154 AC: 796 AN: 5170

South Asian (SAS) AF: 0.332 AC: 1591 AN: 4796

European-Finnish (FIN) AF: 0.423 AC: 4460 AN: 10548

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28328 AN: 67964

Other (OTH) AF: 0.338 AC: 715 AN: 2116

Alfa AF: 0.375 Hom.: 50573

Bravo AF: 0.285

Asia WGS AF: 0.271 AC: 943 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	OBESITY (BMIQ14), SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.87
PhyloP100		4.5
Mutation Taster		=98/2	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: rs1421085; hg19: chr16-53800954;