16-53805223-T-C

Variant names:

• chr16-53805223-T-C
• rs8044769
• NM_001080432.3:c.46-4917T>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.46-4917T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 151,898 control chromosomes in the GnomAD database, including 27,563 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 0.59 (27563 hom., cov: 31)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 103 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.758 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.46-4917T>C		intron	N/A	NP_001073901.1
	FTO	NM_001363894.2		c.46-4917T>C		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.46-4917T>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.46-4917T>C		intron	N/A	ENSP00000418823.1
	FTO	ENST00000637969.1	TSL:5	c.46-4917T>C		intron	N/A	ENSP00000490516.1
	FTO	ENST00000637001.1	TSL:5	c.46-4917T>C		intron	N/A	ENSP00000489936.1

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89696 AN: 151780 Hom.: 27518 Cov.: 31

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.579

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

GnomAD4 genome AF: 0.591 AC: 89789 AN: 151898 Hom.: 27563 Cov.: 31 AF XY: 0.587 AC XY: 43570 AN XY: 74254

African (AFR) AF: 0.765 AC: 31686 AN: 41418

American (AMR) AF: 0.475 AC: 7256 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 2101 AN: 3472

East Asian (EAS) AF: 0.651 AC: 3340 AN: 5134

South Asian (SAS) AF: 0.544 AC: 2621 AN: 4822

European-Finnish (FIN) AF: 0.503 AC: 5289 AN: 10524

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

European-Non Finnish (NFE) AF: 0.526 AC: 35704 AN: 67934

Other (OTH) AF: 0.579 AC: 1223 AN: 2114

Alfa AF: 0.540 Hom.: 93891

Bravo AF: 0.596

Asia WGS AF: 0.617 AC: 2144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.017
DANN	Benign	0.40
PhyloP100		-1.9
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: rs8044769; hg19: chr16-53839135;