16-89884630-A-G

Variant names:

• chr16-89884630-A-G
• NM_014972.3:c.403A>G

Variant summary

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

The NM_014972.3(TCF25):​c.403A>G​(p.Lys135Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF25 NM_014972.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.88

Genes affected

TCF25 (HGNC:29181): (transcription factor 25) TCF25 is a member of the basic helix-loop-helix (bHLH) family of transcription factors that are important in embryonic development (Steen and Lindholm, 2008 [PubMed 18068114]).[supplied by OMIM, Sep 2008]

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=0.28909138).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF25	NM_014972.3	c.403A>G	p.Lys135Glu	missense_variant	Exon 3 of 18	ENST00000263346.13	NP_055787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF25	ENST00000263346.13	c.403A>G	p.Lys135Glu	missense_variant	Exon 3 of 18	1	NM_014972.3	ENSP00000263346.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.403A>G (p.K135E) alteration is located in exon 3 (coding exon 3) of the TCF25 gene. This alteration results from a A to G substitution at nucleotide position 403, causing the lysine (K) at amino acid position 135 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.8	.;M;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	D;N;.;D;N
REVEL	Benign	0.14
Sift	Uncertain	0.019	D;T;.;D;D
Sift4G	Uncertain	0.035	D;T;T;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.38, 0.44
MutPred		0.20		Loss of methylation at K135 (P = 0.0185);Loss of methylation at K135 (P = 0.0185);Loss of methylation at K135 (P = 0.0185);Loss of methylation at K135 (P = 0.0185);Loss of methylation at K135 (P = 0.0185);
MVP		0.63
MPC		0.39
ClinPred		0.86	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-89951038;