19-1611724-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_003200.5(TCF3):​c.1948C>A​(p.Pro650Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,613,622 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

TCF3
NM_003200.5 missense

Scores

3
6
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 7.34
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.015075773).
BP6
Variant 19-1611724-G-T is Benign according to our data. Variant chr19-1611724-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 709097.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000125 (19/152238) while in subpopulation EAS AF= 0.00289 (15/5182). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TCF3NM_003200.5 linkc.1948C>A p.Pro650Thr missense_variant Exon 19 of 19 ENST00000262965.12 NP_003191.1 P15923-1
TCF3NM_001136139.4 linkc.1939C>A p.Pro647Thr missense_variant Exon 19 of 20 ENST00000588136.7 NP_001129611.1 P15923-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TCF3ENST00000262965.12 linkc.1948C>A p.Pro650Thr missense_variant Exon 19 of 19 1 NM_003200.5 ENSP00000262965.5 P15923-1
TCF3ENST00000588136.7 linkc.1939C>A p.Pro647Thr missense_variant Exon 19 of 20 2 NM_001136139.4 ENSP00000468487.1 P15923-2

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152120
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00289
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000200
AC:
50
AN:
250136
Hom.:
0
AF XY:
0.000162
AC XY:
22
AN XY:
135464
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00229
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000193
AC:
282
AN:
1461384
Hom.:
1
Cov.:
31
AF XY:
0.000197
AC XY:
143
AN XY:
726982
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00569
Gnomad4 SAS exome
AF:
0.000220
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152238
Hom.:
0
Cov.:
31
AF XY:
0.000148
AC XY:
11
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00289
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000340
Hom.:
0
Bravo
AF:
0.000117
ExAC
AF:
0.000206
AC:
25
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Jun 03, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Nov 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Sep 16, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1948C>A (p.P650T) alteration is located in exon 19 (coding exon 18) of the TCF3 gene. This alteration results from a C to A substitution at nucleotide position 1948, causing the proline (P) at amino acid position 650 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Agammaglobulinemia 8, autosomal dominant;C5676958:Agammaglobulinemia 8b, autosomal recessive Benign:1
Oct 19, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D;T;T;D;T;T;.;.;.
Eigen
Uncertain
0.30
Eigen_PC
Benign
0.18
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
D;D;D;.;D;D;D;D;D
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.015
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Uncertain
2.2
M;.;.;M;.;.;.;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-5.1
D;.;.;.;.;.;.;.;D
REVEL
Benign
0.24
Sift
Benign
0.059
T;.;.;.;.;.;.;.;D
Sift4G
Uncertain
0.012
D;D;T;D;D;T;T;D;D
Polyphen
1.0
D;.;.;D;.;.;.;D;.
Vest4
0.74
MutPred
0.37
.;.;.;.;.;.;.;.;Gain of glycosylation at P654 (P = 0.0215);
MVP
0.61
MPC
0.28
ClinPred
0.23
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.28
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs7252811; hg19: chr19-1611723; COSMIC: COSV53647056; COSMIC: COSV53647056; API