16-53761497-G-C

Variant names:

• chr16-53761497-G-C
• rs9940700
• NM_001080432.3:c.46-48643G>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.46-48643G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 152,014 control chromosomes in the GnomAD database, including 9,667 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 0.31 (9667 hom., cov: 32)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTO	NM_001080432.3	c.46-48643G>C		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.46-48643G>C		intron_variant	Intron 1 of 8	1	NM_001080432.3	ENSP00000418823.1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46530 AN: 151898 Hom.: 9633 Cov.: 32

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.282

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

GnomAD4 genome AF: 0.307 AC: 46612 AN: 152014 Hom.: 9667 Cov.: 32 AF XY: 0.299 AC XY: 22221 AN XY: 74286

African (AFR) AF: 0.592 AC: 24528 AN: 41414

American (AMR) AF: 0.182 AC: 2777 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 789 AN: 3470

East Asian (EAS) AF: 0.294 AC: 1522 AN: 5176

South Asian (SAS) AF: 0.243 AC: 1170 AN: 4822

European-Finnish (FIN) AF: 0.148 AC: 1568 AN: 10562

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13404 AN: 67980

Other (OTH) AF: 0.285 AC: 601 AN: 2110

Alfa AF: 0.242 Hom.: 728

Bravo AF: 0.319

Asia WGS AF: 0.284 AC: 988 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		1.7
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: rs9940700; hg19: chr16-53795409;