16-54063422-G-C

Variant names:

• chr16-54063422-G-C
• rs2540784
• NM_001080432.3:c.1365-48340G>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.1365-48340G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 152,218 control chromosomes in the GnomAD database, including 665 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 0.076 (665 hom., cov: 32)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90
• 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

LOC105371271 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTO	NM_001080432.3	c.1365-48340G>C		intron_variant	Intron 8 of 8	ENST00000471389.6	NP_001073901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTO	ENST00000471389.6	c.1365-48340G>C		intron_variant	Intron 8 of 8	1	NM_001080432.3	ENSP00000418823.1

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11534 AN: 152100 Hom.: 662 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.0866

Gnomad FIN AF: 0.0555

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0656

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

GnomAD4 genome AF: 0.0759 AC: 11548 AN: 152218 Hom.: 665 Cov.: 32 AF XY: 0.0779 AC XY: 5797 AN XY: 74436

African (AFR) AF: 0.151 AC: 6266 AN: 41522

American (AMR) AF: 0.0503 AC: 769 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3472

East Asian (EAS) AF: 0.142 AC: 735 AN: 5176

South Asian (SAS) AF: 0.0868 AC: 418 AN: 4814

European-Finnish (FIN) AF: 0.0555 AC: 589 AN: 10604

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0370 AC: 2515 AN: 68018

Other (OTH) AF: 0.0649 AC: 137 AN: 2110

Alfa AF: 0.0272 Hom.: 20

Bravo AF: 0.0774

Asia WGS AF: 0.0930 AC: 323 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.020
DANN	Benign	0.46
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: rs2540784; hg19: chr16-54097334;