19-1624008-A-G

Position:

• chr19-1624008-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.500-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,612,132 control chromosomes in the GnomAD database, including 53,848 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5966 hom., cov: 32)
  • Exomes 𝑓: 0.24 (47882 hom.)
• Consequence: TCF3 NM_003200.5 splice_region, intron
• Scores: Splicing: ADA: 0.000006873
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0580

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-1624008-A-G is Benign according to our data. Variant chr19-1624008-A-G is described in ClinVar as [Benign]. Clinvar id is 1169441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF3	NM_003200.5	c.500-8T>C		splice_region_variant, intron_variant		ENST00000262965.12	NP_003191.1
TCF3	NM_001136139.4	c.500-8T>C		splice_region_variant, intron_variant		ENST00000588136.7	NP_001129611.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF3	ENST00000262965.12	c.500-8T>C		splice_region_variant, intron_variant		1	NM_003200.5	ENSP00000262965.5
TCF3	ENST00000588136.7	c.500-8T>C		splice_region_variant, intron_variant		2	NM_001136139.4	ENSP00000468487.1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40159 AN: 151892 Hom.: 5964 Cov.: 32

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.239

GnomAD3 exomes AF: 0.267 AC: 66492 AN: 249182 Hom.: 10815 AF XY: 0.264 AC XY: 35670 AN XY: 135154

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.677

Gnomad SAS exome AF: 0.279

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.242 AC: 353195 AN: 1460122 Hom.: 47882 Cov.: 33 AF XY: 0.242 AC XY: 176093 AN XY: 726340

Gnomad4 AFR exome AF: 0.304

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.694

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.222

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.258

GnomAD4 genome AF: 0.264 AC: 40189 AN: 152010 Hom.: 5966 Cov.: 32 AF XY: 0.269 AC XY: 20018 AN XY: 74306

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.238

Alfa AF: 0.230 Hom.: 1641

Bravo AF: 0.269

Asia WGS AF: 0.432 AC: 1502 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 45% of patients studied by a panel of primary immunodeficiencies. Number of patients: 43. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.4
DANN	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000069
dbscSNV1_RF	Benign	0.0
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: rs55677929; hg19: chr19-1624007; COSMIC: COSV53650692; COSMIC: COSV53650692;