16-54072059-G-A

Variant names:

• chr16-54072059-G-A
• rs2540766
• NM_001080432.3:c.1365-39703G>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.1365-39703G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0992 in 152,132 control chromosomes in the GnomAD database, including 1,246 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 0.099 (1246 hom., cov: 32)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: FTO NM_001080432.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0430
• 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

LOC105371271 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 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.1365-39703G>A		intron	N/A	NP_001073901.1
	FTO	NM_001363894.2		c.1428-39703G>A		intron	N/A	NP_001350823.1
	FTO	NM_001363891.2		c.1395-39703G>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.1365-39703G>A		intron	N/A	ENSP00000418823.1
	FTO	ENST00000268349.7	TSL:1	c.98-39703G>A		intron	N/A	ENSP00000268349.7
	FTO	ENST00000463855.1	TSL:1	c.231-39703G>A		intron	N/A	ENSP00000417843.1

Frequencies

GnomAD3 genomes AF: 0.0991 AC: 15060 AN: 152006 Hom.: 1238 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0586

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.0894

Gnomad FIN AF: 0.0609

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0433

Gnomad OTH AF: 0.0804

GnomAD4 exome AF: 0.125 AC: 1 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 6

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 1 AN: 6

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0992 AC: 15097 AN: 152124 Hom.: 1246 Cov.: 32 AF XY: 0.100 AC XY: 7435 AN XY: 74376

African (AFR) AF: 0.221 AC: 9150 AN: 41462

American (AMR) AF: 0.0585 AC: 894 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3470

East Asian (EAS) AF: 0.141 AC: 731 AN: 5172

South Asian (SAS) AF: 0.0899 AC: 432 AN: 4806

European-Finnish (FIN) AF: 0.0609 AC: 646 AN: 10604

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0433 AC: 2948 AN: 68006

Other (OTH) AF: 0.0795 AC: 168 AN: 2112

Alfa AF: 0.0512 Hom.: 171

Bravo AF: 0.103

Asia WGS AF: 0.101 AC: 351 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.2
DANN	Benign	0.75
PhyloP100		-0.043
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: rs2540766; hg19: chr16-54105971;