16-53704192-G-T

Variant names:

• chr16-53704192-G-T
• rs1161946063
• NM_001080432.3:c.8G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080432.3(FTO):​c.8G>T​(p.Arg3Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000129 in 1,551,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FTO NM_001080432.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.92
• Publications: 3 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32902777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FTO	NM_001080432.3	c.8G>T	p.Arg3Leu	missense_variant	Exon 1 of 9	ENST00000471389.6	NP_001073901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FTO	ENST00000471389.6	c.8G>T	p.Arg3Leu	missense_variant	Exon 1 of 9	1	NM_001080432.3	ENSP00000418823.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399166 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 690112

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

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078816

Other (OTH) AF: 0.00 AC: 0 AN: 57986

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D;T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.0	.;L;.;.;.
PhyloP100		3.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	.;D;.;.;.
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	.;D;.;.;.
Sift4G	Uncertain	0.012	.;D;.;.;.
Polyphen		1.0	.;D;.;.;.
Vest4		0.51
MutPred		0.16		Loss of MoRF binding (P = 0.017);Loss of MoRF binding (P = 0.017);Loss of MoRF binding (P = 0.017);Loss of MoRF binding (P = 0.017);Loss of MoRF binding (P = 0.017);
MVP		0.88
MPC		0.84
ClinPred		0.99	D
GERP RS		6.0
PromoterAI		0.086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.59
Mutation Taster		=46/54	disease causing

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: rs1161946063; hg19: chr16-53738104;