6-133889429-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003206.4(TCF21):c.32A>G(p.Asp11Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TCF21 NM_003206.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF21	NM_003206.4	c.32A>G	p.Asp11Gly	missense_variant	1/2	ENST00000367882.5
TCF21	NM_198392.3	c.32A>G	p.Asp11Gly	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF21	ENST00000367882.5	c.32A>G	p.Asp11Gly	missense_variant	1/2	1	NM_003206.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461870 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2023

The c.32A>G (p.D11G) alteration is located in exon 1 (coding exon 1) of the TCF21 gene. This alteration results from a A to G substitution at nucleotide position 32, causing the aspartic acid (D) at amino acid position 11 to be replaced by a glycine (G). 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	Benign	0.28
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.60
Sift	Benign	0.098	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.73	P;P
Vest4		0.67
MutPred		0.42		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);
MVP		0.79
MPC		0.92
ClinPred		0.81	D
GERP RS		4.4
Varity_R		0.40
gMVP		0.37

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

LitVar

Other links and lift over

dbSNP: rs1286616251; hg19: chr6-134210567; COSMIC: COSV52818670; COSMIC: COSV52818670;