20-604625-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004609.4(TCF15):​c.566G>T​(p.Arg189Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,554,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

TCF15
NM_004609.4 missense

Scores

8
5
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.46
Variant links:
Genes affected
TCF15 (HGNC:11627): (transcription factor 15) The protein encoded by this gene is found in the nucleus and may be involved in the early transcriptional regulation of patterning of the mesoderm. The encoded basic helix-loop-helix protein requires dimerization with another basic helix-loop-helix protein for efficient DNA binding. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.41219878).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TCF15NM_004609.4 linkc.566G>T p.Arg189Met missense_variant Exon 2 of 2 ENST00000246080.4 NP_004600.3 Q12870A4LBB6Q6NVX3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TCF15ENST00000246080.4 linkc.566G>T p.Arg189Met missense_variant Exon 2 of 2 1 NM_004609.4 ENSP00000246080.3 Q12870

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000279
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000815
AC:
13
AN:
159480
Hom.:
0
AF XY:
0.0000711
AC XY:
6
AN XY:
84434
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000393
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000193
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000262
AC:
367
AN:
1402092
Hom.:
0
Cov.:
31
AF XY:
0.000264
AC XY:
183
AN XY:
691912
show subpopulations
Gnomad4 AFR exome
AF:
0.0000316
Gnomad4 AMR exome
AF:
0.0000274
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000405
Gnomad4 NFE exome
AF:
0.000326
Gnomad4 OTH exome
AF:
0.000189
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000279
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000228
Hom.:
0
Bravo
AF:
0.000178
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000596
AC:
5
ExAC
AF:
0.0000924
AC:
10

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.566G>T (p.R189M) alteration is located in exon 2 (coding exon 2) of the TCF15 gene. This alteration results from a G to T substitution at nucleotide position 566, causing the arginine (R) at amino acid position 189 to be replaced by a methionine (M). 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
Pathogenic
0.68
BayesDel_addAF
Uncertain
0.097
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
26
DANN
Benign
0.96
DEOGEN2
Benign
0.32
T
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.67
T
M_CAP
Pathogenic
0.37
D
MetaRNN
Benign
0.41
T
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.4
M
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-2.0
N
REVEL
Pathogenic
0.65
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.45
MVP
0.68
MPC
2.2
ClinPred
0.26
T
GERP RS
5.1
Varity_R
0.39
gMVP
0.64

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

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

Other links and lift over

dbSNP: rs199584509; hg19: chr20-585269; API