chr16-53704192-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001080432.3(FTO):ā€‹c.8G>Cā€‹(p.Arg3Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000286 in 1,399,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000029 ( 0 hom. )

Consequence

FTO
NM_001080432.3 missense

Scores

3
12
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.92
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FTONM_001080432.3 linkuse as main transcriptc.8G>C p.Arg3Pro missense_variant 1/9 ENST00000471389.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FTOENST00000471389.6 linkuse as main transcriptc.8G>C p.Arg3Pro missense_variant 1/91 NM_001080432.3 P1Q9C0B1-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000647
AC:
1
AN:
154588
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
81506
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000439
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000286
AC:
4
AN:
1399166
Hom.:
0
Cov.:
30
AF XY:
0.00000145
AC XY:
1
AN XY:
690112
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000379
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 02, 2023This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 3 of the FTO protein (p.Arg3Pro). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with FTO-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
.;D;T;.;T
Eigen
Uncertain
0.62
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Benign
0.54
D
LIST_S2
Uncertain
0.89
D;D;D;D;D
M_CAP
Benign
0.052
D
MetaRNN
Uncertain
0.48
T;T;T;T;T
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Benign
1.0
.;L;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-2.5
.;N;.;.;.
REVEL
Uncertain
0.35
Sift
Pathogenic
0.0
.;D;.;.;.
Sift4G
Uncertain
0.010
.;D;.;.;.
Polyphen
1.0
.;D;.;.;.
Vest4
0.52
MutPred
0.24
Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);
MVP
0.89
MPC
0.91
ClinPred
0.97
D
GERP RS
6.0
Varity_R
0.54
gMVP
0.64

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1161946063; hg19: chr16-53738104; API