rs6499640

Variant names:

• chr16-53735765-G-A
• rs6499640
• NM_001080432.3:c.45+31536G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001080432.3(FTO):​c.45+31536G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 151,980 control chromosomes in the GnomAD database, including 26,551 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 0.58 (26551 hom., cov: 31)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.995
• Publications: 113 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTO	NM_001080432.3	c.45+31536G>A		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.45+31536G>A		intron_variant	Intron 1 of 8	1	NM_001080432.3	ENSP00000418823.1

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88541 AN: 151862 Hom.: 26535 Cov.: 31

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.582

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

GnomAD4 genome AF: 0.583 AC: 88598 AN: 151980 Hom.: 26551 Cov.: 31 AF XY: 0.578 AC XY: 42922 AN XY: 74278

African (AFR) AF: 0.646 AC: 26766 AN: 41454

American (AMR) AF: 0.460 AC: 7033 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 2039 AN: 3472

East Asian (EAS) AF: 0.177 AC: 911 AN: 5160

South Asian (SAS) AF: 0.495 AC: 2383 AN: 4810

European-Finnish (FIN) AF: 0.571 AC: 6015 AN: 10536

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41517 AN: 67954

Other (OTH) AF: 0.580 AC: 1227 AN: 2114

Alfa AF: 0.590 Hom.: 120532

Bravo AF: 0.571

Asia WGS AF: 0.359 AC: 1254 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.75
DANN	Benign	0.48
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6499640; hg19: chr16-53769677;