rs2074888

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003200.5(TCF3):c.1475C>T(p.Ala492Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,574,730 control chromosomes in the GnomAD database, including 4,192 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A492A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.035 ( 501 hom., cov: 32)

Exomes 𝑓: 0.023 ( 3691 hom. )

Consequence

TCF3
NM_003200.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:3

Conservation

PhyloP100: 1.13

Publications

18 publications found

Variant links:

Genes affected

TCF3 (HGNC:11633): (transcription factor 3) This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription factors. E proteins activate transcription by binding to regulatory E-box sequences on target genes as heterodimers or homodimers, and are inhibited by heterodimerization with inhibitor of DNA-binding (class IV) helix-loop-helix proteins. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T lymphocyte development. Deletion of this gene or diminished activity of the encoded protein may play a role in lymphoid malignancies. This gene is also involved in several chromosomal translocations that are associated with lymphoid malignancies including pre-B-cell acute lymphoblastic leukemia (t(1;19), with PBX1), childhood leukemia (t(19;19), with TFPT) and acute leukemia (t(12;19), with ZNF384). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Sep 2011]

TCF3 Gene-Disease associations (from GenCC):

autosomal agammaglobulinemia
Inheritance: SD, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
agammaglobulinemia 8, autosomal dominant
Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

TCF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016615391).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF3	NM_003200.5 link	c.1475C>T	p.Ala492Val	missense_variant	Exon 17 of 19	ENST00000262965.12	NP_003191.1
TCF3	NM_001136139.4 link	c.1475C>T	p.Ala492Val	missense_variant	Exon 17 of 20	ENST00000588136.7	NP_001129611.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF3	ENST00000262965.12 link	c.1475C>T	p.Ala492Val	missense_variant	Exon 17 of 19	1	NM_003200.5	ENSP00000262965.5
TCF3	ENST00000588136.7 link	c.1475C>T	p.Ala492Val	missense_variant	Exon 17 of 20	2	NM_001136139.4	ENSP00000468487.1

Frequencies

GnomAD3 genomes

AF:

0.0346

AC:

5256

AN:

152030

Hom.:

503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0811

Gnomad ASJ

AF:

0.0533

Gnomad EAS

AF:

0.389

Gnomad SAS

AF:

0.0767

Gnomad FIN

AF:

0.00490

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00507

Gnomad OTH

AF:

0.0378

GnomAD2 exomes

AF:

0.0594

AC:

13197

AN:

222056

AF XY:

0.0571

show subpopulations

Gnomad AFR exome

AF:

0.0258

Gnomad AMR exome

AF:

0.0779

Gnomad ASJ exome

AF:

0.0545

Gnomad EAS exome

AF:

0.407

Gnomad FIN exome

AF:

0.00458

Gnomad NFE exome

AF:

0.00611

Gnomad OTH exome

AF:

0.0364

GnomAD4 exome

AF:

0.0230

AC:

32660

AN:

1422582

Hom.:

3691

Cov.:

AF XY:

0.0239

AC XY:

16746

AN XY:

701578

show subpopulations

African (AFR)

AF:

0.0235

AC:

772

AN:

32900

American (AMR)

AF:

0.0760

AC:

3231

AN:

42518

Ashkenazi Jewish (ASJ)

AF:

0.0511

AC:

1205

AN:

23568

East Asian (EAS)

AF:

0.397

AC:

15547

AN:

39204

South Asian (SAS)

AF:

0.0648

AC:

5150

AN:

79498

European-Finnish (FIN)

AF:

0.00428

AC:

220

AN:

51426

Middle Eastern (MID)

AF:

0.0279

AC:

156

AN:

5600

European-Non Finnish (NFE)

AF:

0.00391

AC:

4258

AN:

1089142

Other (OTH)

AF:

0.0361

AC:

2121

AN:

58726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

1623

3247

4870

6494

8117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.0345

AC:

5250

AN:

152148

Hom.:

501

Cov.:

AF XY:

0.0389

AC XY:

2890

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0238

AC:

989

AN:

41532

American (AMR)

AF:

0.0810

AC:

1238

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0533

AC:

185

AN:

3472

East Asian (EAS)

AF:

0.389

AC:

1986

AN:

5100

South Asian (SAS)

AF:

0.0765

AC:

369

AN:

4822

European-Finnish (FIN)

AF:

0.00490

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00507

AC:

345

AN:

67994

Other (OTH)

AF:

0.0369

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

219

438

657

876

1095

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0197

Hom.:

1139

Bravo

AF:

0.0410

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.0250

AC:

110

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.0509

AC:

6170

Asia WGS

AF:

0.181

AC:

626

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Myeloproliferative neoplasm, unclassifiable

Pathogenic:1

Aug 25, 2022

Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.28

T;T;T;T;T;T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.64

T;T;T;.;T;T;D;T;T

MetaRNN

Benign

0.0017

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-2.1

N;.;.;N;.;.;.;N;.

PhyloP100

1.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.2

N;.;.;.;.;.;.;.;N

REVEL

Benign

0.17

Sift

Benign

0.44

T;.;.;.;.;.;.;.;T

Sift4G

Benign

0.28

T;T;T;T;T;T;T;T;T

Polyphen

0.0010

B;.;.;B;.;.;.;B;.

Vest4

0.083

MPC

0.036

ClinPred

0.0077

GERP RS

1.9

PromoterAI

0.0048

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.016

gMVP

0.31

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over