rs758917874

Variant names:

• chr19-1611712-T-C
• rs758917874
• NM_003200.5:c.1960A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-1611712-T-C
• chr19-1611712-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003200.5(TCF3):​c.1960A>G​(p.Met654Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,674 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TCF3 NM_003200.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26596364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF3	NM_003200.5	c.1960A>G	p.Met654Val	missense_variant	Exon 19 of 19	ENST00000262965.12	NP_003191.1
TCF3	NM_001136139.4	c.1951A>G	p.Met651Val	missense_variant	Exon 19 of 20	ENST00000588136.7	NP_001129611.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF3	ENST00000262965.12	c.1960A>G	p.Met654Val	missense_variant	Exon 19 of 19	1	NM_003200.5	ENSP00000262965.5
TCF3	ENST00000588136.7	c.1951A>G	p.Met651Val	missense_variant	Exon 19 of 20	2	NM_001136139.4	ENSP00000468487.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460674 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Pathogenic	0.81	D;T;T;D;T;T;.;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.8	D;.;.;.;.;.;.;.;D
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;.;.;.;.;.;.;.;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;D
Polyphen		0.083	B;.;.;B;.;.;.;B;.
Vest4		0.33
MVP		0.32
MPC		0.040
ClinPred		0.67	D
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs758917874; hg19: chr19-1611711;