rs2074888

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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:2

Conservation

PhyloP100: 1.13

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 links:

TCF3 (HGNC:):

TCF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
TCF3	NM_003200.5 linkuse as main transcript	c.1475C>T	p.Ala492Val	missense_variant	17/19	ENST00000262965.12	NP_003191.1	P15923-1
TCF3	NM_001136139.4 linkuse as main transcript	c.1475C>T	p.Ala492Val	missense_variant	17/20	ENST00000588136.7	NP_001129611.1	P15923-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF3	ENST00000262965.12 linkuse as main transcript	c.1475C>T	p.Ala492Val	missense_variant	17/19	1	NM_003200.5	ENSP00000262965.5		P15923-1
TCF3	ENST00000588136.7 linkuse as main transcript	c.1475C>T	p.Ala492Val	missense_variant	17/20	2	NM_001136139.4	ENSP00000468487.1		P15923-2

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

GnomAD3 exomes

AF:

0.0594

AC:

13197

AN:

222056

Hom.:

1736

AF XY:

0.0571

AC XY:

6718

AN XY:

117754

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 SAS exome

AF:

0.0677

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

Gnomad4 AFR exome

AF:

0.0235

Gnomad4 AMR exome

AF:

0.0760

Gnomad4 ASJ exome

AF:

0.0511

Gnomad4 EAS exome

AF:

0.397

Gnomad4 SAS exome

AF:

0.0648

Gnomad4 FIN exome

AF:

0.00428

Gnomad4 NFE exome

AF:

0.00391

Gnomad4 OTH exome

AF:

0.0361

GnomAD4 genome

AF:

0.0345

AC:

5250

AN:

152148

Hom.:

501

Cov.:

AF XY:

0.0389

AC XY:

2890

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0238

Gnomad4 AMR

AF:

0.0810

Gnomad4 ASJ

AF:

0.0533

Gnomad4 EAS

AF:

0.389

Gnomad4 SAS

AF:

0.0765

Gnomad4 FIN

AF:

0.00490

Gnomad4 NFE

AF:

0.00507

Gnomad4 OTH

AF:

0.0369

Alfa

AF:

0.0158

Hom.:

351

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:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Myeloproliferative neoplasm, unclassifiable

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology

Aug 25, 2022

- -

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

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;.

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.016

gMVP

0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over