19-1650135-A-G

Position:

• chr19-1650135-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003200.5(TCF3):​c.72+42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 1,515,796 control chromosomes in the GnomAD database, including 183,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27521 hom., cov: 32)
  • Exomes 𝑓: 0.46 (155861 hom.)
• Consequence: TCF3 NM_003200.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.25

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 19-1650135-A-G is Benign according to our data. Variant chr19-1650135-A-G is described in ClinVar as [Benign]. Clinvar id is 1185424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF3	NM_003200.5	c.72+42T>C		intron_variant		ENST00000262965.12	NP_003191.1
TCF3	NM_001136139.4	c.72+42T>C		intron_variant		ENST00000588136.7	NP_001129611.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF3	ENST00000262965.12	c.72+42T>C		intron_variant		1	NM_003200.5	ENSP00000262965.5
TCF3	ENST00000588136.7	c.72+42T>C		intron_variant		2	NM_001136139.4	ENSP00000468487.1

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86587 AN: 151790 Hom.: 27479 Cov.: 32

Gnomad AFR AF: 0.829

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.532

GnomAD3 exomes AF: 0.541 AC: 81014 AN: 149844 Hom.: 24617 AF XY: 0.543 AC XY: 43388 AN XY: 79958

Gnomad AFR exome AF: 0.839

Gnomad AMR exome AF: 0.631

Gnomad ASJ exome AF: 0.397

Gnomad EAS exome AF: 0.869

Gnomad SAS exome AF: 0.703

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.461 AC: 628144 AN: 1363888 Hom.: 155861 Cov.: 24 AF XY: 0.466 AC XY: 314227 AN XY: 674408

Gnomad4 AFR exome AF: 0.845

Gnomad4 AMR exome AF: 0.627

Gnomad4 ASJ exome AF: 0.407

Gnomad4 EAS exome AF: 0.903

Gnomad4 SAS exome AF: 0.700

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.413

Gnomad4 OTH exome AF: 0.494

GnomAD4 genome AF: 0.571 AC: 86686 AN: 151908 Hom.: 27521 Cov.: 32 AF XY: 0.576 AC XY: 42813 AN XY: 74286

Gnomad4 AFR AF: 0.830

Gnomad4 AMR AF: 0.582

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.889

Gnomad4 SAS AF: 0.716

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.413

Gnomad4 OTH AF: 0.530

Alfa AF: 0.438 Hom.: 20112

Bravo AF: 0.593

Asia WGS AF: 0.785 AC: 2727 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 80% of patients studied by a panel of primary immunodeficiencies. Number of patients: 76. Only high quality variants are reported. -

Agammaglobulinemia 8, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.62

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: rs1860661; hg19: chr19-1650134; COSMIC: COSV53647954;