16-54118136-A-T

Variant names:

• chr16-54118136-A-T
• rs11076023
• NM_001080432.3:c.*6221A>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.*6221A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 151,928 control chromosomes in the GnomAD database, including 19,041 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 0.49 (19041 hom., cov: 31)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: FTO NM_001080432.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.188
• Publications: 18 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.631 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.*6221A>T		3_prime_UTR	Exon 9 of 9	NP_001073901.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTO	ENST00000471389.6	TSL:1 MANE Select	c.*6221A>T		3_prime_UTR	Exon 9 of 9	ENSP00000418823.1
	FTO	ENST00000637969.1	TSL:5	c.1492+6247A>T		intron	N/A	ENSP00000490516.1
	FTO	ENST00000612285.2	TSL:5	c.517+6247A>T		intron	N/A	ENSP00000490300.1

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74403 AN: 151808 Hom.: 19001 Cov.: 31

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.458

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

⚠️ 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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

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: 0.490 AC: 74499 AN: 151926 Hom.: 19041 Cov.: 31 AF XY: 0.494 AC XY: 36708 AN XY: 74264

African (AFR) AF: 0.638 AC: 26415 AN: 41408

American (AMR) AF: 0.441 AC: 6740 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1402 AN: 3466

East Asian (EAS) AF: 0.553 AC: 2841 AN: 5142

South Asian (SAS) AF: 0.392 AC: 1889 AN: 4824

European-Finnish (FIN) AF: 0.504 AC: 5314 AN: 10552

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28545 AN: 67942

Other (OTH) AF: 0.457 AC: 962 AN: 2106

Alfa AF: 0.465 Hom.: 1861

Bravo AF: 0.494

Asia WGS AF: 0.454 AC: 1577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.2
DANN	Benign	0.67
PhyloP100		0.19
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: rs11076023; hg19: chr16-54152048;