NM_001080432.3:c.46-46487A>G

Variant names:

• chr16-53763653-A-G
• rs4784323
• NM_001080432.3:c.46-46487A>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.46-46487A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 152,118 control chromosomes in the GnomAD database, including 41,943 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 0.74 (41943 hom., cov: 32)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 19 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.874 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.46-46487A>G		intron	N/A	NP_001073901.1
	FTO	NM_001363894.2		c.46-46487A>G		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.46-46487A>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.46-46487A>G		intron	N/A	ENSP00000418823.1
	FTO	ENST00000637969.1	TSL:5	c.46-46487A>G		intron	N/A	ENSP00000490516.1
	FTO	ENST00000637001.1	TSL:5	c.46-46487A>G		intron	N/A	ENSP00000489936.1

Frequencies

GnomAD3 genomes AF: 0.736 AC: 111841 AN: 151996 Hom.: 41884 Cov.: 32

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.722

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.727

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

GnomAD4 genome AF: 0.736 AC: 111958 AN: 152118 Hom.: 41943 Cov.: 32 AF XY: 0.734 AC XY: 54578 AN XY: 74352

African (AFR) AF: 0.881 AC: 36607 AN: 41530

American (AMR) AF: 0.722 AC: 11033 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2483 AN: 3470

East Asian (EAS) AF: 0.763 AC: 3940 AN: 5166

South Asian (SAS) AF: 0.642 AC: 3098 AN: 4828

European-Finnish (FIN) AF: 0.653 AC: 6883 AN: 10548

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.670 AC: 45520 AN: 67970

Other (OTH) AF: 0.730 AC: 1543 AN: 2114

Alfa AF: 0.664 Hom.: 15214

Bravo AF: 0.748

Asia WGS AF: 0.740 AC: 2571 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.0
DANN	Benign	0.77
PhyloP100		-1.4
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: rs4784323; hg19: chr16-53797565;