16-53769126-A-G

Variant names:

• chr16-53769126-A-G
• rs16952520
• NM_001080432.3:c.46-41014A>G

Variant summary

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

The NM_001080432.3(FTO):​c.46-41014A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 152,162 control chromosomes in the GnomAD database, including 2,049 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 0.12 (2049 hom., cov: 32)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 6 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=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.424 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.46-41014A>G		intron	N/A	NP_001073901.1
	FTO	NM_001363894.2		c.46-41014A>G		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.46-41014A>G		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.46-41014A>G		intron	N/A	ENSP00000418823.1
	FTO	ENST00000637969.1	TSL:5	c.46-41014A>G		intron	N/A	ENSP00000490516.1
	FTO	ENST00000637001.1	TSL:5	c.46-41014A>G		intron	N/A	ENSP00000489936.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18050 AN: 152044 Hom.: 2043 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0898

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.0645

Gnomad FIN AF: 0.0505

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0383

Gnomad OTH AF: 0.103

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

GnomAD4 genome AF: 0.119 AC: 18090 AN: 152162 Hom.: 2049 Cov.: 32 AF XY: 0.120 AC XY: 8923 AN XY: 74384

African (AFR) AF: 0.257 AC: 10648 AN: 41480

American (AMR) AF: 0.0896 AC: 1370 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3472

East Asian (EAS) AF: 0.439 AC: 2269 AN: 5168

South Asian (SAS) AF: 0.0650 AC: 314 AN: 4830

European-Finnish (FIN) AF: 0.0505 AC: 536 AN: 10604

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0383 AC: 2607 AN: 68012

Other (OTH) AF: 0.103 AC: 216 AN: 2106

Alfa AF: 0.0685 Hom.: 3408

Bravo AF: 0.132

Asia WGS AF: 0.243 AC: 845 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.78
PhyloP100		2.2
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: rs16952520; hg19: chr16-53803038;