chr19-1615797-G-T

Variant names:

• chr19-1615797-G-T
• rs2074888
• NM_003200.5:c.1475C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF3 NM_003200.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13

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]

ACMG classification

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=0.14159513).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422608 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 701588

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 32

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	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
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	N
LIST_S2	Benign	0.83	T;T;T;.;T;T;D;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.093	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.;N;.;.;.;N;.
PrimateAI	Uncertain	0.55	T
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
Polyphen		0.11	B;.;.;B;.;.;.;B;.
Vest4		0.26
MutPred		0.39		.;Gain of solvent accessibility (P = 0.005);.;.;.;.;.;.;Gain of solvent accessibility (P = 0.005);
MVP		0.34
MPC		0.049
ClinPred		0.11	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.042
gMVP		0.29

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

Other links and lift over

dbSNP: rs2074888; hg19: chr19-1615796;