16-53779538-A-T

Variant names:

• chr16-53779538-A-T
• rs8043757
• NM_001080432.3:c.46-30602A>T

Variant summary

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

The NM_001080432.3(FTO):​c.46-30602A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 151,962 control chromosomes in the GnomAD database, including 11,934 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 0.39 (11934 hom., cov: 31)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.386
• Publications: 70 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTO	NM_001080432.3	c.46-30602A>T		intron_variant	Intron 1 of 8	ENST00000471389.6	NP_001073901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTO	ENST00000471389.6	c.46-30602A>T		intron_variant	Intron 1 of 8	1	NM_001080432.3	ENSP00000418823.1

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59446 AN: 151846 Hom.: 11924 Cov.: 31

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.389

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

GnomAD4 genome AF: 0.391 AC: 59475 AN: 151962 Hom.: 11934 Cov.: 31 AF XY: 0.388 AC XY: 28817 AN XY: 74282

African (AFR) AF: 0.420 AC: 17389 AN: 41440

American (AMR) AF: 0.309 AC: 4727 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1752 AN: 3468

East Asian (EAS) AF: 0.153 AC: 788 AN: 5162

South Asian (SAS) AF: 0.316 AC: 1525 AN: 4822

European-Finnish (FIN) AF: 0.400 AC: 4208 AN: 10532

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27729 AN: 67946

Other (OTH) AF: 0.390 AC: 823 AN: 2112

Alfa AF: 0.408 Hom.: 1590

Bravo AF: 0.381

Asia WGS AF: 0.288 AC: 1003 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.60
PhyloP100		-0.39
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: rs8043757; hg19: chr16-53813450;