chr16-54004059-T-G

Variant names:

• chr16-54004059-T-G
• rs4784338
• NM_001080432.3:c.1364+69950T>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.1364+69950T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 152,042 control chromosomes in the GnomAD database, including 38,028 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 0.69 (38028 hom., cov: 32)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.935
• Publications: 10 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.878 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.1364+69950T>G		intron	N/A	NP_001073901.1
	FTO	NM_001363894.2		c.1427+69950T>G		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.1394+69950T>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.1364+69950T>G		intron	N/A	ENSP00000418823.1
	FTO	ENST00000268349.7	TSL:1	c.97+19105T>G		intron	N/A	ENSP00000268349.7
	FTO	ENST00000463855.1	TSL:1	c.230+69950T>G		intron	N/A	ENSP00000417843.1

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105497 AN: 151924 Hom.: 37961 Cov.: 32

Gnomad AFR AF: 0.885

Gnomad AMI AF: 0.745

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.637

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

GnomAD4 genome AF: 0.695 AC: 105637 AN: 152042 Hom.: 38028 Cov.: 32 AF XY: 0.698 AC XY: 51865 AN XY: 74334

African (AFR) AF: 0.885 AC: 36712 AN: 41478

American (AMR) AF: 0.645 AC: 9847 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2149 AN: 3472

East Asian (EAS) AF: 0.455 AC: 2356 AN: 5182

South Asian (SAS) AF: 0.752 AC: 3621 AN: 4816

European-Finnish (FIN) AF: 0.721 AC: 7610 AN: 10554

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.605 AC: 41145 AN: 67956

Other (OTH) AF: 0.638 AC: 1343 AN: 2104

Alfa AF: 0.666 Hom.: 4857

Bravo AF: 0.695

Asia WGS AF: 0.649 AC: 2254 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.73
PhyloP100		-0.94
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: rs4784338; hg19: chr16-54037971;