NM_001136139.4:c.1663G>A

Variant names:

• chr19-1612357-C-T
• rs879255271
• NM_001136139.4:c.1663G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 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. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004020919: This variant was 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). PMID:24216514" and additional evidence is available in ClinVar. 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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• autosomal agammaglobulinemia

  Inheritance: AD, SD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• agammaglobulinemia 8, autosomal dominant

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• agammaglobulinemia 8b, autosomal recessive

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004020919: This variant was 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). PMID: 24216514; SCV002169003: Experimental studies have shown that this missense change affects TCF3 function (PMID: 24216514).; SCV003560427: "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." PMID:23824624
• 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 VariationId is 225870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136139.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF3	NM_001136139.4	MANE Plus Clinical	c.1663G>A	p.Glu555Lys	missense	Exon 18 of 20	NP_001129611.1	P15923-2
	TCF3	NM_003200.5	MANE Select	c.1823-508G>A		intron	N/A	NP_003191.1	P15923-1
	TCF3	NM_001351779.2		c.1663G>A	p.Glu555Lys	missense	Exon 18 of 19	NP_001338708.1	P15923-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF3	ENST00000588136.7	TSL:2 MANE Plus Clinical	c.1663G>A	p.Glu555Lys	missense	Exon 18 of 20	ENSP00000468487.1	P15923-2
	TCF3	ENST00000262965.12	TSL:1 MANE Select	c.1823-508G>A		intron	N/A	ENSP00000262965.5	P15923-1
	TCF3	ENST00000610756.4	TSL:1	n.1181-508G>A		intron	N/A

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Agammaglobulinemia 8, autosomal dominant (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		7.7
PrimateAI	Pathogenic	0.93	D
REVEL	Pathogenic	0.99
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.99
ClinPred		0.78	D
GERP RS		4.6
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879255271; hg19: chr19-1612356;