Genetic Variant TCF21:p.Asp21Glu (chr6-133889460-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003206.4(TCF21):c.63C>G(p.Asp21Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 1,614,060 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0059 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 82 hom. )

Consequence

TCF21
NM_003206.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -0.402

Publications

8 publications found

Variant links:

Genes affected

TCF21 (HGNC:11632): (transcription factor 21) TCF21 encodes a transcription factor of the basic helix-loop-helix family. The TCF21 product is mesoderm specific, and expressed in embryonic epicardium, mesenchyme-derived tissues of lung, gut, gonad, and both mesenchymal and glomerular epithelial cells in the kidney. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

TCF21 links:

TARID (HGNC:50506): (TCF21 antisense RNA inducing promoter demethylation)

TARID links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035883188).

BS2

High AC in GnomAd4 at 894 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF21	NM_003206.4 link	c.63C>G	p.Asp21Glu	missense_variant	Exon 1 of 2	ENST00000367882.5	NP_003197.2	O43680
TCF21	NM_198392.3 link	c.63C>G	p.Asp21Glu	missense_variant	Exon 1 of 3		NP_938206.1	O43680

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF21	ENST00000367882.5 link	c.63C>G	p.Asp21Glu	missense_variant	Exon 1 of 2	1	NM_003206.4	ENSP00000356857.5		O43680

Frequencies

GnomAD3 genomes

AF:

0.00588

AC:

894

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00136

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00321

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00933

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00587

AC:

1476

AN:

251472

AF XY:

0.00604

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00411

Gnomad NFE exome

AF:

0.00957

Gnomad OTH exome

AF:

0.00766

GnomAD4 exome

AF:

0.00896

AC:

13096

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00856

AC XY:

6222

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

33480

American (AMR)

AF:

0.00273

AC:

122

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00291

AC:

AN:

26136

East Asian (EAS)

AF:

0.000327

AC:

AN:

39700

South Asian (SAS)

AF:

0.00294

AC:

254

AN:

86258

European-Finnish (FIN)

AF:

0.00522

AC:

279

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0107

AC:

11886

AN:

1112010

Other (OTH)

AF:

0.00684

AC:

413

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

852

1705

2557

3410

4262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

452

904

1356

1808

2260

<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:

0.00588

AC:

894

AN:

152168

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

414

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00246

AC:

102

AN:

41520

American (AMR)

AF:

0.00510

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.00136

AC:

AN:

5154

South Asian (SAS)

AF:

0.00269

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00321

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00933

AC:

634

AN:

67980

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00875

Hom.:

Bravo

AF:

0.00571

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00570

AC:

692

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00987

EpiControl

AF:

0.00848

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 01, 2014

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

8.3

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.58

.;T

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

0.55

N;N

PhyloP100

-0.40

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.23

Sift

Benign

0.39

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.14

B;B

Vest4

0.044

MutPred

0.68

Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);

MVP

0.58

MPC

0.66

ClinPred

0.0015

GERP RS

0.58

PromoterAI

-0.070

Neutral

(source)

Varity_R

0.041

gMVP

0.12

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over