chr16-53704185-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001080432.3(FTO):ā€‹c.1A>Gā€‹(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000322 in 1,551,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

FTO
NM_001080432.3 start_lost

Scores

6
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.12
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Start lost variant, no new inframe start found.
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.1A>G p.Met1? start_lost 1/9 ENST00000471389.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FTOENST00000471389.6 linkuse as main transcriptc.1A>G p.Met1? start_lost 1/91 NM_001080432.3 P1Q9C0B1-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152230
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000214
AC:
3
AN:
1399200
Hom.:
0
Cov.:
30
AF XY:
0.00000290
AC XY:
2
AN XY:
690124
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000280
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000185
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152348
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

Lethal polymalformative syndrome, Boissel type Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 26, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.50
.;T;T;.;T
Eigen
Uncertain
0.66
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Benign
0.57
D
LIST_S2
Uncertain
0.90
D;D;D;D;D
M_CAP
Pathogenic
0.60
D
MetaRNN
Uncertain
0.64
D;D;D;D;D
MetaSVM
Uncertain
-0.12
T
MutationTaster
Benign
1.0
D;D
PROVEAN
Benign
-1.3
.;N;.;.;.
REVEL
Uncertain
0.38
Sift
Pathogenic
0.0
.;D;.;.;.
Sift4G
Pathogenic
0.0
.;D;.;.;.
Polyphen
0.97
.;D;.;.;.
Vest4
0.95
MutPred
0.54
Loss of catalytic residue at M1 (P = 0.0103);Loss of catalytic residue at M1 (P = 0.0103);Loss of catalytic residue at M1 (P = 0.0103);Loss of catalytic residue at M1 (P = 0.0103);Loss of catalytic residue at M1 (P = 0.0103);
MVP
0.85
ClinPred
1.0
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.51

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: rs534074284; hg19: chr16-53738097; API