Genetic Variant TCF3:p.Ala492Glu (chr19-1615797-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003200.5(TCF3):c.1475C>A(p.Ala492Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A492V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TCF3
NM_003200.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14159513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF3	NM_003200.5 link	c.1475C>A	p.Ala492Glu	missense_variant	Exon 17 of 19	ENST00000262965.12	NP_003191.1
TCF3	NM_001136139.4 link	c.1475C>A	p.Ala492Glu	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>A	p.Ala492Glu	missense_variant	Exon 17 of 19	1	NM_003200.5	ENSP00000262965.5
TCF3	ENST00000588136.7 link	c.1475C>A	p.Ala492Glu	missense_variant	Exon 17 of 20	2	NM_001136139.4	ENSP00000468487.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

222056

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1422608

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701588

African (AFR)

AF:

0.00

AC:

AN:

32900

American (AMR)

AF:

0.00

AC:

AN:

42530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23568

East Asian (EAS)

AF:

0.00

AC:

AN:

39210

South Asian (SAS)

AF:

0.00

AC:

AN:

79504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5600

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089146

Other (OTH)

AF:

0.00

AC:

AN:

58726

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

1139

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.39

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

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.0094

MetaRNN

Benign

0.093

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

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

PhyloP100

1.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.6

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

REVEL

Benign

0.17

Sift

Benign

0.46

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

Sift4G

Benign

0.58

T;T;T;T;T;D;D;T;T

Vest4

0.26

ClinPred

0.11

GERP RS

1.9

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.042

gMVP

0.29

Mutation Taster

=94/6

polymorphism

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over