19-1611727-T-G

Position:

chr19-1611727-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000262965.12(TCF3):c.1945A>C(p.Asn649His) variant causes a missense change. The variant allele was found at a frequency of 0.0000266 in 1,613,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TCF3
ENST00000262965.12 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.71

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09896958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF3	NM_003200.5 linkuse as main transcript	c.1945A>C	p.Asn649His	missense_variant	19/19	ENST00000262965.12	NP_003191.1
TCF3	NM_001136139.4 linkuse as main transcript	c.1936A>C	p.Asn646His	missense_variant	19/20	ENST00000588136.7	NP_001129611.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF3	ENST00000262965.12 linkuse as main transcript	c.1945A>C	p.Asn649His	missense_variant	19/19	1	NM_003200.5	ENSP00000262965	A1	P15923-1
TCF3	ENST00000588136.7 linkuse as main transcript	c.1936A>C	p.Asn646His	missense_variant	19/20	2	NM_001136139.4	ENSP00000468487	P3	P15923-2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000532

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000440

AC:

AN:

250268

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135544

show subpopulations

Gnomad AFR exome

AF:

0.000556

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:

0.0000123

AC:

AN:

1461432

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.0000895

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000164

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000530

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

TCF3-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2022

The TCF3 c.1945A>C variant is predicted to result in the amino acid substitution p.Asn649His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-1611726-T-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TCF3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 1045821). This variant has not been reported in the literature in individuals affected with TCF3-related conditions. This variant is present in population databases (rs372296344, gnomAD 0.06%). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 649 of the TCF3 protein (p.Asn649His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

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

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;D;.;D;D;D;D;D

M_CAP

Benign

0.055

MetaRNN

Benign

0.099

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

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.5

M;.;.;M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.8

D;.;.;.;.;.;.;.;D

REVEL

Benign

0.18

Sift

Uncertain

0.0010

D;.;.;.;.;.;.;.;D

Sift4G

Benign

0.072

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

Polyphen

1.0

D;.;.;D;.;.;.;D;.

Vest4

0.48

MVP

0.67

MPC

0.043

ClinPred

0.36

GERP RS

3.6

Varity_R

0.58

gMVP

0.69

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

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