Genetic Variant TCF21:p.Asp21Glu (chr6-133889460-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003206.4(TCF21):c.63C>A(p.Asp21Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TCF21
NM_003206.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09275854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF21	NM_003206.4 link	c.63C>A	p.Asp21Glu	missense_variant	Exon 1 of 2	ENST00000367882.5	NP_003197.2	O43680
TCF21	NM_198392.3 link	c.63C>A	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>A	p.Asp21Glu	missense_variant	Exon 1 of 2	1	NM_003206.4	ENSP00000356857.5		O43680

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251472

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.26

CADD

Benign

7.8

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.58

.;T

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.093

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

0.21

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

0.039

GERP RS

0.58

PromoterAI

-0.060

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over