Genetic Variant TET3:c.360+47G>A (chr2-74003213-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001287491.2(TET3):c.360+47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00696 in 1,547,692 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0072 ( 48 hom. )

Consequence

TET3
NM_001287491.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.281

Publications

0 publications found

Variant links:

Genes affected

TET3 (HGNC:28313): (tet methylcytosine dioxygenase 3) Enables methyl-CpG binding activity and zinc ion binding activity. Involved in histone H3-K4 trimethylation; positive regulation of transcription by RNA polymerase II; and protein O-linked glycosylation. Predicted to be located in cytoplasm and male pronucleus. Predicted to be active in nucleus. Biomarker of esophagus squamous cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

TET3 Gene-Disease associations (from GenCC):

Beck-Fahrner syndrome
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, G2P, Illumina, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

TET3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 2-74003213-G-A is Benign according to our data. Variant chr2-74003213-G-A is described in ClinVar as Benign. ClinVar VariationId is 1342286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00459 (697/151998) while in subpopulation NFE AF = 0.00792 (538/67956). AF 95% confidence interval is 0.00736. There are 2 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,SD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287491.2. 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
	TET3	NM_001287491.2	MANE Select	c.360+47G>A		intron	N/A	NP_001274420.1	O43151-1
	TET3	NM_001366022.1		c.81+47G>A		intron	N/A	NP_001352951.1	A0A5H1ZRP3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TET3	ENST00000409262.8	TSL:1 MANE Select	c.360+47G>A	intron	N/A	ENSP00000386869.3	O43151-1
TET3	ENST00000305799.9	TSL:5	c.81+47G>A	intron	N/A	ENSP00000307803.8	A0A5H1ZRP3
TET3	ENST00000718303.1		c.-81+47G>A	intron	N/A	ENSP00000520736.1	A0ABB0MVC9

Frequencies

GnomAD3 genomes

AF:

0.00459

AC:

697

AN:

151880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00333

Gnomad FIN

AF:

0.00161

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00792

Gnomad OTH

AF:

0.00532

GnomAD2 exomes

AF:

0.00486

AC:

705

AN:

145128

AF XY:

0.00487

show subpopulations

Gnomad AFR exome

AF:

0.000890

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.00314

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00785

Gnomad OTH exome

AF:

0.00615

GnomAD4 exome

AF:

0.00722

AC:

10080

AN:

1395694

Hom.:

Cov.:

AF XY:

0.00715

AC XY:

4920

AN XY:

688344

show subpopulations

African (AFR)

AF:

0.000951

AC:

AN:

31560

American (AMR)

AF:

0.00407

AC:

145

AN:

35626

Ashkenazi Jewish (ASJ)

AF:

0.00354

AC:

AN:

25118

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35684

South Asian (SAS)

AF:

0.00435

AC:

344

AN:

79012

European-Finnish (FIN)

AF:

0.00233

AC:

112

AN:

48064

Middle Eastern (MID)

AF:

0.00827

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00830

AC:

8938

AN:

1077072

Other (OTH)

AF:

0.00646

AC:

374

AN:

57878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

516

1031

1547

2062

2578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

336

672

1008

1344

1680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00459

AC:

697

AN:

151998

Hom.:

Cov.:

AF XY:

0.00416

AC XY:

309

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41448

American (AMR)

AF:

0.00295

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00333

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00792

AC:

538

AN:

67956

Other (OTH)

AF:

0.00526

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00589

Hom.:

Bravo

AF:

0.00481

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Beck-Fahrner syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

0.28

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over