rs2287142

Variant names:

• chr16-53911439-G-A
• rs2287142
• ENST00000463855.1:c.60G>A
• FTO p.Lys20Lys

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000463855.1(FTO):​c.60G>A​(p.Lys20Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 703,074 control chromosomes in the GnomAD database, including 3,228 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 0.029 (383 hom., cov: 32)
  • Exomes 𝑓: 0.045 (2845 hom.)
• Consequence: FTO ENST00000463855.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.767
• Publications: 9 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP7: Synonymous conserved (PhyloP=-0.767 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000463855.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTO	NM_001080432.3	MANE Select	c.1239+22488G>A		intron	N/A	NP_001073901.1	Q9C0B1-1
	FTO	NM_001363894.2		c.1302+10737G>A		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.1269+22488G>A		intron	N/A	NP_001350820.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTO	ENST00000463855.1	TSL:1	c.60G>A	p.Lys20Lys	synonymous	Exon 1 of 3	ENSP00000417843.1	Q9C0B1-2
	FTO	ENST00000471389.6	TSL:1 MANE Select	c.1239+22488G>A		intron	N/A	ENSP00000418823.1	Q9C0B1-1
	FTO	ENST00000637969.1	TSL:5	c.1239+22488G>A		intron	N/A	ENSP00000490516.1	A0A1B0GVH5

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4352 AN: 152174 Hom.: 375 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.0795

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0743 AC: 10205 AN: 137312 AF XY: 0.0679

Gnomad AFR exome AF: 0.00386

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.000962

Gnomad EAS exome AF: 0.321

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.0435

GnomAD4 exome AF: 0.0450 AC: 24782 AN: 550780 Hom.: 2845 Cov.: 0 AF XY: 0.0444 AC XY: 13249 AN XY: 298148

African (AFR) AF: 0.00386 AC: 61 AN: 15808

American (AMR) AF: 0.186 AC: 6452 AN: 34714

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 36 AN: 20030

East Asian (EAS) AF: 0.342 AC: 10966 AN: 32098

South Asian (SAS) AF: 0.0665 AC: 4175 AN: 62752

European-Finnish (FIN) AF: 0.0281 AC: 948 AN: 33706

Middle Eastern (MID) AF: 0.00442 AC: 18 AN: 4076

European-Non Finnish (NFE) AF: 0.00300 AC: 951 AN: 316980

Other (OTH) AF: 0.0384 AC: 1175 AN: 30616

GnomAD4 genome AF: 0.0287 AC: 4364 AN: 152294 Hom.: 383 Cov.: 32 AF XY: 0.0331 AC XY: 2463 AN XY: 74462

African (AFR) AF: 0.00452 AC: 188 AN: 41558

American (AMR) AF: 0.105 AC: 1611 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.312 AC: 1616 AN: 5172

South Asian (SAS) AF: 0.0790 AC: 381 AN: 4824

European-Finnish (FIN) AF: 0.0299 AC: 317 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00250 AC: 170 AN: 68034

Other (OTH) AF: 0.0350 AC: 74 AN: 2116

Alfa AF: 0.0221 Hom.: 174

Bravo AF: 0.0375

Asia WGS AF: 0.178 AC: 620 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.040
DANN	Benign	0.31
PhyloP100		-0.77
PromoterAI		-0.0044	Neutral
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2287142;

hg19: chr16-53945351;

COSMIC: COSV67110764;