Genetic Variant TCF15:p.Gly175Arg (chr20-609715-C-T) – ACMG Classification: Benign (-8 pts)

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

Splicing: ADA: 0.5590

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]

TCF15 links:

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
TCF15	NM_004609.4 link	c.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
TCF15	ENST00000246080.4 link	c.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.:

Cov.:

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:

AN:

14150

Hom.:

AF XY:

0.000683

AC XY:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.000102

ExAC

AF:

0.000237

AC:

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

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.0088

MetaSVM

Uncertain

0.43

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.53

REVEL

Uncertain

0.40

Sift

Benign

0.36

Sift4G

Benign

0.61

Polyphen

0.98

Vest4

0.38

MutPred

0.29

Gain of solvent accessibility (P = 0.019);

MVP

0.38

MPC

1.4

ClinPred

0.13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over