chr16-53763606-T-C

Variant names:

• chr16-53763606-T-C
• rs6499643
• NM_001080432.3:c.46-46534T>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.46-46534T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,128 control chromosomes in the GnomAD database, including 4,744 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 0.23 (4744 hom., cov: 32)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.685
• Publications: 8 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P

LOC124903691 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.379 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTO	NM_001080432.3	MANE Select	c.46-46534T>C		intron	N/A	NP_001073901.1	Q9C0B1-1
	FTO	NM_001363894.2		c.46-46534T>C		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.46-46534T>C		intron	N/A	NP_001350820.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTO	ENST00000471389.6	TSL:1 MANE Select	c.46-46534T>C		intron	N/A	ENSP00000418823.1	Q9C0B1-1
	FTO	ENST00000637969.1	TSL:5	c.46-46534T>C		intron	N/A	ENSP00000490516.1	A0A1B0GVH5
	FTO	ENST00000918264.1		c.46-46534T>C		intron	N/A	ENSP00000588323.1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34706 AN: 152008 Hom.: 4731 Cov.: 32

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.212

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

GnomAD4 genome AF: 0.228 AC: 34757 AN: 152128 Hom.: 4744 Cov.: 32 AF XY: 0.224 AC XY: 16681 AN XY: 74364

African (AFR) AF: 0.384 AC: 15914 AN: 41448

American (AMR) AF: 0.155 AC: 2367 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3470

East Asian (EAS) AF: 0.145 AC: 752 AN: 5186

South Asian (SAS) AF: 0.217 AC: 1046 AN: 4830

European-Finnish (FIN) AF: 0.112 AC: 1188 AN: 10592

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11990 AN: 67998

Other (OTH) AF: 0.217 AC: 458 AN: 2112

Alfa AF: 0.193 Hom.: 5228

Bravo AF: 0.235

Asia WGS AF: 0.201 AC: 696 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.6
DANN	Benign	0.47
PhyloP100		0.69
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: rs6499643; hg19: chr16-53797518;