Genetic Variant TCF15:p.Ala79Ser (chr20-610003-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_004609.4(TCF15):c.235G>T(p.Ala79Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000054 in 1,334,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

TCF15
NM_004609.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.63

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.788

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004609.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF15	NM_004609.4	MANE Select	c.235G>T	p.Ala79Ser	missense	Exon 1 of 2	NP_004600.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF15	ENST00000246080.4	TSL:1 MANE Select	c.235G>T	p.Ala79Ser	missense	Exon 1 of 2	ENSP00000246080.3	Q12870

Frequencies

GnomAD3 genomes

AF:

0.0000403

AC:

AN:

148740

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000901

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000370

AC:

AN:

54072

AF XY:

0.0000321

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000915

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000557

AC:

AN:

1185544

Hom.:

Cov.:

AF XY:

0.0000658

AC XY:

AN XY:

577388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25288

American (AMR)

AF:

0.000144

AC:

AN:

20856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18874

East Asian (EAS)

AF:

0.00

AC:

AN:

26194

South Asian (SAS)

AF:

0.00

AC:

AN:

45616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3334

European-Non Finnish (NFE)

AF:

0.0000648

AC:

AN:

971892

Other (OTH)

AF:

0.00

AC:

AN:

47428

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000403

AC:

AN:

148846

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

72520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41206

American (AMR)

AF:

0.00

AC:

AN:

15028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000901

AC:

AN:

66560

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.79

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

PhyloP100

5.6

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.47

MutPred

0.47

Gain of phosphorylation at A79 (P = 0.0241)

MVP

0.87

MPC

2.3

ClinPred

0.56

GERP RS

4.5

PromoterAI

0.028

Neutral

(source)

Varity_R

0.78

gMVP

0.30

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over