19-1611712-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003200.5(TCF3):c.1960A>C(p.Met654Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,674 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M654I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TCF3 NM_003200.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

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=0.10590002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF3	NM_003200.5	c.1960A>C	p.Met654Leu	missense_variant	19/19	ENST00000262965.12
TCF3	NM_001136139.4	c.1951A>C	p.Met651Leu	missense_variant	19/20	ENST00000588136.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF3	ENST00000262965.12	c.1960A>C	p.Met654Leu	missense_variant	19/19	1	NM_003200.5	A1
TCF3	ENST00000588136.7	c.1951A>C	p.Met651Leu	missense_variant	19/20	2	NM_001136139.4	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000281 AC: 7 AN: 249552 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135186

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 SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460674 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726598

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: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 654 of the TCF3 protein (p.Met654Leu). This variant is present in population databases (rs758917874, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TCF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 2081063). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	8.2
Dann	Benign	0.74
DEOGEN2	Benign	0.37	T;T;T;T;T;T;.;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.86
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N;.;.;N;.;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N;.;.;.;.;.;.;.;N
REVEL	Benign	0.23
Sift	Benign	0.34	T;.;.;.;.;.;.;.;T
Sift4G	Benign	0.44	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;B;.;.;.;B;.
Vest4		0.19
MutPred		0.44		.;.;.;.;.;.;.;.;Gain of stability (P = 0.0174);
MVP		0.076
MPC		0.034
ClinPred		0.024	T
GERP RS		-3.5
Varity_R		0.10
gMVP		0.45

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: rs758917874; hg19: chr19-1611711;