10-68572834-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_030625.3(TET1):c.496C>T(p.Leu166Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000601 in 1,614,146 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: TET1 NM_030625.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.172

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TET1
• BP4: Computational evidence support a benign effect (MetaRNN=0.00445804).
• BP6: Variant 10-68572834-C-T is Benign according to our data. Variant chr10-68572834-C-T is described in ClinVar as [Benign]. Clinvar id is 721836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TET1	NM_030625.3	c.496C>T	p.Leu166Phe	missense_variant	2/12	ENST00000373644.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TET1	ENST00000373644.5	c.496C>T	p.Leu166Phe	missense_variant	2/12	1	NM_030625.3	P1

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 510 AN: 152162 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.00287

GnomAD3 exomes AF: 0.000715 AC: 179 AN: 250336 Hom.: 1 AF XY: 0.000531 AC XY: 72 AN XY: 135506

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000313 AC: 458 AN: 1461866 Hom.: 2 Cov.: 35 AF XY: 0.000286 AC XY: 208 AN XY: 727234

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00336 AC: 512 AN: 152280 Hom.: 2 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74462

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000645 Hom.: 0

Bravo AF: 0.00370

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000881 AC: 107

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TET1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	8.6
Dann	Benign	0.96
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.0080
Sift	Uncertain	0.012	D
Sift4G	Benign	0.079	T
Polyphen		0.17	B
Vest4		0.051
MVP		0.043
MPC		0.076
ClinPred		0.0063	T
GERP RS		0.58
Varity_R		0.042
gMVP		0.029

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: rs115711488; hg19: chr10-70332591; COSMIC: COSV104684820;