chr19-1612357-C-T

Position:

• chr19-1612357-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001136139.4(TCF3):​c.1663G>A​(p.Glu555Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 9/15 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E555E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF3 NM_001136139.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.74

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 19-1612357-C-T is Pathogenic according to our data. Variant chr19-1612357-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 225870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF3	NM_001136139.4	c.1663G>A	p.Glu555Lys	missense_variant	18/20	ENST00000588136.7
TCF3	NM_003200.5	c.1823-508G>A		intron_variant		ENST00000262965.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF3	ENST00000588136.7	c.1663G>A	p.Glu555Lys	missense_variant	18/20	2	NM_001136139.4	P3
TCF3	ENST00000262965.12	c.1823-508G>A		intron_variant		1	NM_003200.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461592 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727082

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Agammaglobulinemia 8, autosomal dominant Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 29, 2023	Variant summary: TCF3 NM_003200.3:c.1823-508G>A, also annotated as NM_001136139.3:c.1663G>A (p.E555K), is located at a position not widely known to affect splicing within one of the alternate transcripts of TCF3. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. As a missense variant in an alternate transcript, TCF3 c.1663G>A (p.Glu555Lys) results in a conservative amino acid change located in the Myc-type, basic helix-loop-helix (bHLH) domain (IPR011598) of the encoded protein sequence. Four of five in-silico tools predict a damaging impact on protein function. The variant was absent in 248552 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in the literature as the missense change p.E555K from the alternate transcript encoding the E47 isoform. This variant was reported in five unrelated heterozygous individuals affected with Agammaglobulinaemia and failure of B-cell development (Boisson_2013, Al_Sheikh_2021), and parental testing suggested this was a de novo mutation in all of the patients. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function for the p.E555K missense change in cells that were transfected with a vector to produce the mutated E47 protein. This demonstrated that the mutant E47 localizes to the nucleus normally but shows substantially reduced binding to the E5 immunoglobulin enhancer probe in vitro compared to the wildtype protein, and exerts a strong dominant negative effect when binding to the probe as a homodimer with wildtype E47 (Boisson_2013). The following publications have been ascertained in the context of this evaluation (PMID: 24216514, 33905048). Three submitters have cited clinical-significance assessments for the variant (in the context of the E47 isoform p.E555K missense change) to ClinVar after 2014, and classified it as pathogenic. Based on the evidence outlined above demonstrating an impact of this nucleotide change to the E47 isoform of TCF3, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 12, 2022	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2021

The c.1663G>A (p.E555K) alteration is located in exon 17 (coding exon 17) of the TCF3 gene. This alteration results from a G to A substitution at nucleotide position 1663, causing the glutamic acid (E) at amino acid position 555 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported de novo in multiple patients with agammaglobulinemia (Boisson, 2013; Al Sheikh, 2021). This amino acid position is highly conserved in available vertebrate species. In vitro functional expression studies and studies of patient cells with the E555K mutant showed that while the E47 transcription factor protein does localize properly to the nucleus, but it did not perform proper DNA binding and acted in a dominant-negative manner when co-expressed with wildtype. The authors concluded that E47 plays a critical role in enforcing the block in development of B cell precursors that lack functional antigen receptors (Boisson, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. Experimental studies have shown that this missense change affects TCF3 function (PMID: 24216514). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 225870). This missense change has been observed in individual(s) with agammaglobulinemia (PMID: 24216514). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 555 of the TCF3 protein (p.Glu555Lys). The TCF3 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001136139.3, and corresponds to NM_003200.4:c.1823-508G>A in the primary transcript. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;D;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
REVEL	Pathogenic	0.99
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.93
MVP		0.99
ClinPred		0.78	D
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879255271; hg19: chr19-1612356;