NM_001080432.3:c.1365-37712A>C

Variant names:

• chr16-54074050-A-C
• rs2540769
• NM_001080432.3:c.1365-37712A>C

Variant summary

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

The NM_001080432.3(FTO):​c.1365-37712A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 151,718 control chromosomes in the GnomAD database, including 8,369 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 0.27 (8369 hom., cov: 30)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• Publications: 11 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.571 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.1365-37712A>C		intron	N/A	NP_001073901.1
	FTO	NM_001363894.2		c.1428-37712A>C		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.1395-37712A>C		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.1365-37712A>C		intron	N/A	ENSP00000418823.1
	FTO	ENST00000268349.7	TSL:1	c.98-37712A>C		intron	N/A	ENSP00000268349.7
	FTO	ENST00000463855.1	TSL:1	c.231-37712A>C		intron	N/A	ENSP00000417843.1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40355 AN: 151600 Hom.: 8326 Cov.: 30

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.0923

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.240

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

GnomAD4 genome AF: 0.267 AC: 40465 AN: 151718 Hom.: 8369 Cov.: 30 AF XY: 0.266 AC XY: 19720 AN XY: 74170

African (AFR) AF: 0.577 AC: 23808 AN: 41278

American (AMR) AF: 0.168 AC: 2554 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 571 AN: 3468

East Asian (EAS) AF: 0.190 AC: 980 AN: 5152

South Asian (SAS) AF: 0.327 AC: 1569 AN: 4802

European-Finnish (FIN) AF: 0.116 AC: 1219 AN: 10522

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9091 AN: 67944

Other (OTH) AF: 0.246 AC: 519 AN: 2106

Alfa AF: 0.172 Hom.: 1722

Bravo AF: 0.281

Asia WGS AF: 0.280 AC: 974 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	8.5
DANN	Benign	0.44
PhyloP100		0.24
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: rs2540769; hg19: chr16-54107962;