19-1624008-A-G

Variant names:

• chr19-1624008-A-G
• rs55677929
• NM_003200.5:c.500-8T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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: Benign. The variant received -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 VariationId 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.

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.500-8T>C		splice_region intron	N/A	NP_003191.1	P15923-1
	TCF3	NM_001136139.4	MANE Plus Clinical	c.500-8T>C		splice_region intron	N/A	NP_001129611.1	P15923-2
	TCF3	NM_001351778.2		c.500-8T>C		splice_region 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.500-8T>C		splice_region intron	N/A	ENSP00000262965.5	P15923-1
	TCF3	ENST00000588136.7	TSL:2 MANE Plus Clinical	c.500-8T>C		splice_region intron	N/A	ENSP00000468487.1	P15923-2
	TCF3	ENST00000931972.1		c.587-8T>C		splice_region intron	N/A	ENSP00000602031.1

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

GnomAD2 exomes AF: 0.267 AC: 66492 AN: 249182 AF XY: 0.264

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 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

African (AFR) AF: 0.304 AC: 10168 AN: 33460

American (AMR) AF: 0.233 AC: 10382 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 6836 AN: 26122

East Asian (EAS) AF: 0.694 AC: 27513 AN: 39652

South Asian (SAS) AF: 0.277 AC: 23826 AN: 86132

European-Finnish (FIN) AF: 0.222 AC: 11709 AN: 52774

Middle Eastern (MID) AF: 0.223 AC: 1287 AN: 5766

European-Non Finnish (NFE) AF: 0.221 AC: 245922 AN: 1111272

Other (OTH) AF: 0.258 AC: 15552 AN: 60320

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

African (AFR) AF: 0.297 AC: 12298 AN: 41436

American (AMR) AF: 0.268 AC: 4093 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 913 AN: 3470

East Asian (EAS) AF: 0.670 AC: 3451 AN: 5148

South Asian (SAS) AF: 0.296 AC: 1423 AN: 4814

European-Finnish (FIN) AF: 0.228 AC: 2415 AN: 10572

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14839 AN: 67970

Other (OTH) AF: 0.238 AC: 503 AN: 2112

Alfa AF: 0.229 Hom.: 2197

Bravo AF: 0.269

Asia WGS AF: 0.432 AC: 1502 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.4
DANN	Benign	0.31
PhyloP100		-0.058
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55677929; hg19: chr19-1624007; COSMIC: COSV53650692; COSMIC: COSV53650692;