rs12446228

Variant names:

• chr16-53766475-A-G
• rs12446228
• NM_001080432.3:c.46-43665A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-53766475-A-G
• chr16-53766475-A-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.46-43665A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 152,038 control chromosomes in the GnomAD database, including 34,441 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 0.67 (34441 hom., cov: 31)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.502
• Publications: 15 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.754 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.46-43665A>G		intron	N/A	NP_001073901.1	Q9C0B1-1
	FTO	NM_001363894.2		c.46-43665A>G		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.46-43665A>G		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.46-43665A>G		intron	N/A	ENSP00000418823.1	Q9C0B1-1
	FTO	ENST00000637969.1	TSL:5	c.46-43665A>G		intron	N/A	ENSP00000490516.1	A0A1B0GVH5
	FTO	ENST00000918264.1		c.46-43665A>G		intron	N/A	ENSP00000588323.1

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101495 AN: 151920 Hom.: 34391 Cov.: 31

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.667

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

GnomAD4 genome AF: 0.668 AC: 101594 AN: 152038 Hom.: 34441 Cov.: 31 AF XY: 0.667 AC XY: 49529 AN XY: 74310

African (AFR) AF: 0.761 AC: 31563 AN: 41458

American (AMR) AF: 0.561 AC: 8575 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2719 AN: 3470

East Asian (EAS) AF: 0.760 AC: 3923 AN: 5160

South Asian (SAS) AF: 0.678 AC: 3262 AN: 4814

European-Finnish (FIN) AF: 0.604 AC: 6379 AN: 10568

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.633 AC: 43013 AN: 67972

Other (OTH) AF: 0.672 AC: 1420 AN: 2112

Alfa AF: 0.540 Hom.: 1305

Bravo AF: 0.666

Asia WGS AF: 0.738 AC: 2564 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.8
DANN	Benign	0.31
PhyloP100		-0.50
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: rs12446228; hg19: chr16-53800387;