rs6499642

Variant names:

• chr16-53763594-C-T
• rs6499642
• NM_001080432.3:c.46-46546C>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.46-46546C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0962 in 152,064 control chromosomes in the GnomAD database, including 1,588 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 0.096 (1588 hom., cov: 32)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.856
• Publications: 5 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTO	NM_001080432.3	c.46-46546C>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.46-46546C>T		intron_variant	Intron 1 of 8	1	NM_001080432.3	ENSP00000418823.1

Frequencies

GnomAD3 genomes AF: 0.0961 AC: 14605 AN: 151946 Hom.: 1586 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.0359

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0723

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

GnomAD4 genome AF: 0.0962 AC: 14629 AN: 152064 Hom.: 1588 Cov.: 32 AF XY: 0.0931 AC XY: 6916 AN XY: 74324

African (AFR) AF: 0.270 AC: 11200 AN: 41420

American (AMR) AF: 0.0472 AC: 722 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 105 AN: 3468

East Asian (EAS) AF: 0.0358 AC: 185 AN: 5170

South Asian (SAS) AF: 0.0259 AC: 125 AN: 4824

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10582

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0291 AC: 1977 AN: 68002

Other (OTH) AF: 0.0720 AC: 152 AN: 2110

Alfa AF: 0.0556 Hom.: 1371

Bravo AF: 0.106

Asia WGS AF: 0.0460 AC: 160 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.41
PhyloP100		-0.86
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: rs6499642; hg19: chr16-53797506;