rs9924817

Variant names:

• chr16-53774012-G-A
• rs9924817
• NM_001080432.3:c.46-36128G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001080432.3(FTO):​c.46-36128G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00712 in 152,170 control chromosomes in the GnomAD database, including 15 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 0.0071 (15 hom., cov: 33)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 2 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=-0.48).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00712 (1083/152170) while in subpopulation AFR AF = 0.0245 (1018/41532). AF 95% confidence interval is 0.0233. There are 15 homozygotes in GnomAd4. There are 488 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

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.46-36128G>A		intron	N/A	NP_001073901.1
	FTO	NM_001363894.2		c.46-36128G>A		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.46-36128G>A		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.46-36128G>A		intron	N/A	ENSP00000418823.1
	FTO	ENST00000637969.1	TSL:5	c.46-36128G>A		intron	N/A	ENSP00000490516.1
	FTO	ENST00000637001.1	TSL:5	c.46-36128G>A		intron	N/A	ENSP00000489936.1

Frequencies

GnomAD3 genomes AF: 0.00712 AC: 1083 AN: 152052 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00479

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

GnomAD4 genome AF: 0.00712 AC: 1083 AN: 152170 Hom.: 15 Cov.: 33 AF XY: 0.00656 AC XY: 488 AN XY: 74420

African (AFR) AF: 0.0245 AC: 1018 AN: 41532

American (AMR) AF: 0.00308 AC: 47 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67974

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00380 Hom.: 4

Bravo AF: 0.00833

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.86
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

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: rs9924817; hg19: chr16-53807924;