chr20-609715-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004609.4(TCF15):​c.523G>A​(p.Gly175Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 1,382,968 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00091 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 3 hom. )

Consequence

TCF15
NM_004609.4 missense, splice_region

Scores

2
8
9
Splicing: ADA: 0.5590
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.008794814).
BS2
High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TCF15NM_004609.4 linkc.523G>A p.Gly175Arg missense_variant, splice_region_variant Exon 1 of 2 ENST00000246080.4 NP_004600.3 Q12870A4LBB6Q6NVX3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TCF15ENST00000246080.4 linkc.523G>A p.Gly175Arg missense_variant, splice_region_variant Exon 1 of 2 1 NM_004609.4 ENSP00000246080.3 Q12870

Frequencies

GnomAD3 genomes
AF:
0.000907
AC:
138
AN:
152190
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0106
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000309
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000707
AC:
10
AN:
14150
Hom.:
0
AF XY:
0.000683
AC XY:
6
AN XY:
8788
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00875
Gnomad NFE exome
AF:
0.000274
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000388
AC:
478
AN:
1230662
Hom.:
3
Cov.:
29
AF XY:
0.000369
AC XY:
222
AN XY:
602174
show subpopulations
Gnomad4 AFR exome
AF:
0.0000415
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00876
Gnomad4 NFE exome
AF:
0.000202
Gnomad4 OTH exome
AF:
0.000316
GnomAD4 genome
AF:
0.000906
AC:
138
AN:
152306
Hom.:
1
Cov.:
32
AF XY:
0.00136
AC XY:
101
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0106
Gnomad4 NFE
AF:
0.000309
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000265
Hom.:
0
Bravo
AF:
0.000102
ExAC
AF:
0.000237
AC:
21

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 12, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.523G>A (p.G175R) alteration is located in exon 1 (coding exon 1) of the TCF15 gene. This alteration results from a G to A substitution at nucleotide position 523, causing the glycine (G) at amino acid position 175 to be replaced by an arginine (R). 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
Uncertain
0.40
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.10
T
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.73
T
M_CAP
Pathogenic
0.35
D
MetaRNN
Benign
0.0088
T
MetaSVM
Uncertain
0.43
D
MutationAssessor
Benign
1.4
L
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.53
N
REVEL
Uncertain
0.40
Sift
Benign
0.36
T
Sift4G
Benign
0.61
T
Polyphen
0.98
D
Vest4
0.38
MutPred
0.29
Gain of solvent accessibility (P = 0.019);
MVP
0.38
MPC
1.4
ClinPred
0.13
T
GERP RS
4.3
Varity_R
0.24
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.56
dbscSNV1_RF
Benign
0.68
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: rs761478938; hg19: chr20-590359; API