rs3998860

Positions:

• chr10-68646098-A-G
• chr10-68646098-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030625.3(TET1):​c.3369A>G​(p.Ile1123Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,613,732 control chromosomes in the GnomAD database, including 523,176 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.72 (41118 hom., cov: 31)
  • Exomes 𝑓: 0.81 (482058 hom.)
• Consequence: TET1 NM_030625.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.405

Genes affected

TET1 (HGNC:29484): (tet methylcytosine dioxygenase 1) DNA methylation is an epigenetic mechanism that is important for controlling gene expression. The protein encoded by this gene is a demethylase that belongs to the TET (ten-eleven translocation) family. Members of the TET protein family play a role in the DNA methylation process and gene activation. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0815608E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET1	NM_030625.3	c.3369A>G	p.Ile1123Met	missense_variant	4/12	ENST00000373644.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET1	ENST00000373644.5	c.3369A>G	p.Ile1123Met	missense_variant	4/12	1	NM_030625.3	P1

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109582 AN: 151890 Hom.: 41116 Cov.: 31

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.896

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.761

GnomAD3 exomes AF: 0.777 AC: 194962 AN: 250830 Hom.: 76848 AF XY: 0.783 AC XY: 106246 AN XY: 135696

Gnomad AFR exome AF: 0.485

Gnomad AMR exome AF: 0.724

Gnomad ASJ exome AF: 0.891

Gnomad EAS exome AF: 0.840

Gnomad SAS exome AF: 0.735

Gnomad FIN exome AF: 0.801

Gnomad NFE exome AF: 0.820

Gnomad OTH exome AF: 0.808

GnomAD4 exome AF: 0.810 AC: 1183593 AN: 1461724 Hom.: 482058 Cov.: 60 AF XY: 0.808 AC XY: 587858 AN XY: 727170

Gnomad4 AFR exome AF: 0.488

Gnomad4 AMR exome AF: 0.730

Gnomad4 ASJ exome AF: 0.890

Gnomad4 EAS exome AF: 0.835

Gnomad4 SAS exome AF: 0.740

Gnomad4 FIN exome AF: 0.798

Gnomad4 NFE exome AF: 0.826

Gnomad4 OTH exome AF: 0.809

GnomAD4 genome AF: 0.721 AC: 109626 AN: 152008 Hom.: 41118 Cov.: 31 AF XY: 0.722 AC XY: 53644 AN XY: 74294

Gnomad4 AFR AF: 0.493

Gnomad4 AMR AF: 0.754

Gnomad4 ASJ AF: 0.896

Gnomad4 EAS AF: 0.837

Gnomad4 SAS AF: 0.728

Gnomad4 FIN AF: 0.797

Gnomad4 NFE AF: 0.819

Gnomad4 OTH AF: 0.759

Alfa AF: 0.810 Hom.: 106054

Bravo AF: 0.711

TwinsUK AF: 0.837 AC: 3103

ALSPAC AF: 0.818 AC: 3153

ESP6500AA AF: 0.499 AC: 2200

ESP6500EA AF: 0.835 AC: 7180

ExAC AF: 0.773 AC: 93837

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.060
Sift	Benign	0.16	T
Sift4G	Benign	0.073	T
Polyphen		0.070	B
Vest4		0.034
MPC		0.050
ClinPred		0.0036	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.073
gMVP		0.054

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

Other links and lift over

dbSNP: rs3998860; hg19: chr10-70405855; COSMIC: COSV65385549;