Genetic Variant NM_003200.5:c.*2090T>A (chr19-1609617-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003200.5(TCF3):c.*2090T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0409 in 221,084 control chromosomes in the GnomAD database, including 1,235 homozygotes. 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: 𝑓 0.029 ( 476 hom., cov: 31)

Exomes 𝑓: 0.067 ( 759 hom. )

Consequence

TCF3
NM_003200.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.23

Publications

2 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF3	NM_003200.5 link	c.*2090T>A		3_prime_UTR_variant	Exon 19 of 19	ENST00000262965.12	NP_003191.1	P15923-1
TCF3	NM_001136139.4 link	c.*1756T>A		3_prime_UTR_variant	Exon 20 of 20	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.*2090T>A		3_prime_UTR_variant	Exon 19 of 19	1	NM_003200.5	ENSP00000262965.5		P15923-1
TCF3	ENST00000588136.7 link	c.*1756T>A		3_prime_UTR_variant	Exon 20 of 20	2	NM_001136139.4	ENSP00000468487.1		P15923-2

Frequencies

GnomAD3 genomes

AF:

0.0291

AC:

4420

AN:

151748

Hom.:

478

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00525

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0803

Gnomad ASJ

AF:

0.0519

Gnomad EAS

AF:

0.385

Gnomad SAS

AF:

0.0757

Gnomad FIN

AF:

0.00492

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00503

Gnomad OTH

AF:

0.0316

GnomAD4 exome

AF:

0.0669

AC:

4633

AN:

69218

Hom.:

759

Cov.:

AF XY:

0.0659

AC XY:

2109

AN XY:

32002

show subpopulations

African (AFR)

AF:

0.00379

AC:

AN:

3170

American (AMR)

AF:

0.0710

AC:

145

AN:

2042

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

202

AN:

4378

East Asian (EAS)

AF:

0.384

AC:

3806

AN:

9914

South Asian (SAS)

AF:

0.0623

AC:

AN:

610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.0206

AC:

AN:

436

European-Non Finnish (NFE)

AF:

0.00551

AC:

236

AN:

42836

Other (OTH)

AF:

0.0320

AC:

185

AN:

5778

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

170

341

511

682

852

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.0291

AC:

4416

AN:

151866

Hom.:

476

Cov.:

AF XY:

0.0336

AC XY:

2491

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.00524

AC:

217

AN:

41420

American (AMR)

AF:

0.0802

AC:

1224

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.0519

AC:

180

AN:

3468

East Asian (EAS)

AF:

0.386

AC:

1964

AN:

5092

South Asian (SAS)

AF:

0.0758

AC:

364

AN:

4804

European-Finnish (FIN)

AF:

0.00492

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00503

AC:

342

AN:

67936

Other (OTH)

AF:

0.0308

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

166

333

499

666

832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0120

Hom.:

Bravo

AF:

0.0348

Asia WGS

AF:

0.177

AC:

614

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.2

(source)

DANN

Benign

0.61

PhyloP100

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over