NM_003200.5:c.72+42T>A

Variant names:

• chr19-1650135-A-T
• rs1860661
• NM_003200.5:c.72+42T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003200.5(TCF3):​c.72+42T>A variant causes a intron 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF3 NM_003200.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 20 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003200.5. 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_003200.5	MANE Select	c.72+42T>A		intron	N/A	NP_003191.1	P15923-1
	TCF3	NM_001136139.4	MANE Plus Clinical	c.72+42T>A		intron	N/A	NP_001129611.1	P15923-2
	TCF3	NM_001351778.2		c.72+42T>A		intron	N/A	NP_001338707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF3	ENST00000262965.12	TSL:1 MANE Select	c.72+42T>A		intron	N/A	ENSP00000262965.5	P15923-1
	TCF3	ENST00000588136.7	TSL:2 MANE Plus Clinical	c.72+42T>A		intron	N/A	ENSP00000468487.1	P15923-2
	TCF3	ENST00000931972.1		c.72+42T>A		intron	N/A	ENSP00000602031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.31e-7 AC: 1 AN: 1367404 Hom.: 0 Cov.: 24 AF XY: 0.00000148 AC XY: 1 AN XY: 676024

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31290

American (AMR) AF: 0.00 AC: 0 AN: 35510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24952

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36142

South Asian (SAS) AF: 0.00 AC: 0 AN: 78634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1055296

Other (OTH) AF: 0.00 AC: 0 AN: 57026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.72
PhyloP100		-1.3
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs1860661; hg19: chr19-1650134;