rs73609956

Variant names:

• chr16-53704202-T-C
• rs73609956
• NM_001080432.3:c.18T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001080432.3(FTO):​c.18T>C​(p.Thr6Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,551,466 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (170 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (141 hom.)
• Consequence: FTO NM_001080432.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.452
• Publications: 6 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 16-53704202-T-C is Benign according to our data. Variant chr16-53704202-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 319677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.452 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0875 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTO	NM_001080432.3	MANE Select	c.18T>C	p.Thr6Thr	synonymous	Exon 1 of 9	NP_001073901.1	Q9C0B1-1
	FTO	NM_001363894.2		c.18T>C	p.Thr6Thr	synonymous	Exon 1 of 10	NP_001350823.1
	FTO	NM_001363891.2		c.18T>C	p.Thr6Thr	synonymous	Exon 1 of 9	NP_001350820.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FTO	ENST00000471389.6	TSL:1 MANE Select	c.18T>C	p.Thr6Thr	synonymous	Exon 1 of 9	ENSP00000418823.1	Q9C0B1-1
	FTO	ENST00000637969.1	TSL:5	c.18T>C	p.Thr6Thr	synonymous	Exon 1 of 11	ENSP00000490516.1	A0A1B0GVH5
	FTO	ENST00000918264.1		c.18T>C	p.Thr6Thr	synonymous	Exon 1 of 9	ENSP00000588323.1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3946 AN: 152174 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0901

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00593 AC: 916 AN: 154476 AF XY: 0.00428

Gnomad AFR exome AF: 0.0895

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000324

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00259 AC: 3625 AN: 1399174 Hom.: 141 Cov.: 30 AF XY: 0.00227 AC XY: 1567 AN XY: 690120

African (AFR) AF: 0.0924 AC: 2919 AN: 31588

American (AMR) AF: 0.00479 AC: 171 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: 0.000265 AC: 21 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49256

Middle Eastern (MID) AF: 0.00387 AC: 22 AN: 5692

European-Non Finnish (NFE) AF: 0.000138 AC: 149 AN: 1078814

Other (OTH) AF: 0.00592 AC: 343 AN: 57984

GnomAD4 genome AF: 0.0259 AC: 3947 AN: 152292 Hom.: 170 Cov.: 32 AF XY: 0.0249 AC XY: 1855 AN XY: 74470

African (AFR) AF: 0.0899 AC: 3735 AN: 41550

American (AMR) AF: 0.00915 AC: 140 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68034

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0216 Hom.: 102

Bravo AF: 0.0292

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Joubert syndrome (1)
-	-	1	Lethal polymalformative syndrome, Boissel type (1)
-	-	1	Meckel-Gruber syndrome (1)
-	-	1	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.7
DANN	Benign	0.70
PhyloP100		-0.45
PromoterAI		0.0065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=300/0	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: rs73609956; hg19: chr16-53738114;