19-1611732-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_003200.5(TCF3):c.1940C>G(p.Ala647Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000477 in 1,613,546 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

TCF3
NM_003200.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.11

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03769034).

BP6

Variant 19-1611732-G-C is Benign according to our data. Variant chr19-1611732-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1598229.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000204 (31/152110) while in subpopulation AFR AF= 0.000701 (29/41388). AF 95% confidence interval is 0.0005. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF3	NM_003200.5 link	c.1940C>G	p.Ala647Gly	missense_variant	Exon 19 of 19	ENST00000262965.12	NP_003191.1	P15923-1
TCF3	NM_001136139.4 link	c.1931C>G	p.Ala644Gly	missense_variant	Exon 19 of 20	ENST00000588136.7	NP_001129611.1	P15923-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF3	ENST00000262965.12 link	c.1940C>G	p.Ala647Gly	missense_variant	Exon 19 of 19	1	NM_003200.5	ENSP00000262965.5		P15923-1
TCF3	ENST00000588136.7 link	c.1931C>G	p.Ala644Gly	missense_variant	Exon 19 of 20	2	NM_001136139.4	ENSP00000468487.1		P15923-2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000701

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000961

GnomAD3 exomes

AF:

0.0000639

AC:

AN:

250328

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135566

show subpopulations

Gnomad AFR exome

AF:

0.000865

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461436

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000204

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000701

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000961

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000302

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1940C>G (p.A647G) alteration is located in exon 19 (coding exon 18) of the TCF3 gene. This alteration results from a C to G substitution at nucleotide position 1940, causing the alanine (A) at amino acid position 647 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Feb 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.21

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

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.85

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

M_CAP

Benign

0.0092

MetaRNN

Benign

0.038

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.76

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

PrimateAI

Benign

0.39

PROVEAN

Benign

0.49

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

REVEL

Benign

0.18

Sift

Benign

0.32

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

Sift4G

Benign

0.58

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

Polyphen

0.79

P;.;.;P;.;.;.;B;.

Vest4

0.053

MVP

0.47

MPC

0.14

ClinPred

0.034

GERP RS

3.5

Varity_R

0.048

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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