chr19-1624008-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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: SD, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
agammaglobulinemia 8, autosomal dominant
Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

TCF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF3	NM_003200.5 link	c.500-8T>C		splice_region_variant, intron_variant	Intron 7 of 18	ENST00000262965.12	NP_003191.1	P15923-1
TCF3	NM_001136139.4 link	c.500-8T>C		splice_region_variant, intron_variant	Intron 7 of 19	ENST00000588136.7	NP_001129611.1	P15923-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF3	ENST00000262965.12 link	c.500-8T>C		splice_region_variant, intron_variant	Intron 7 of 18	1	NM_003200.5	ENSP00000262965.5		P15923-1
TCF3	ENST00000588136.7 link	c.500-8T>C		splice_region_variant, intron_variant	Intron 7 of 19	2	NM_001136139.4	ENSP00000468487.1		P15923-2

Frequencies

GnomAD3 genomes

AF:

0.264

AC:

40159

AN:

151892

Hom.:

5964

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.242

AC XY:

176093

AN XY:

726340

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

12279

24558

36838

49117

61396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8748

17496

26244

34992

43740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.264

AC:

40189

AN:

152010

Hom.:

5966

Cov.:

AF XY:

0.269

AC XY:

20018

AN XY:

74306

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.218

AC:

14839

AN:

67970

Other (OTH)

AF:

0.238

AC:

503

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1479

2957

4436

5914

7393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

414

828

1242

1656

2070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.229

Hom.:

2197

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over