NM_001077653.2:c.1329G>A

Variant names:

• chr7-35202445-C-T
• rs1789317610
• NM_001077653.2:c.1329G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001077653.2(TBX20):​c.1329G>A​(p.Met443Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,386,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: TBX20 NM_001077653.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

TBX20 (HGNC:11598): (T-box transcription factor 20) This gene encodes a T-box family member. The T-box family members share a common DNA binding domain, termed the T-box, and they are transcription factors involved in the regulation of developmental processes. This gene is essential for heart development. Mutations in this gene are associated with diverse cardiac pathologies, including defects in septation, valvulogenesis and cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

TBX20 Gene-Disease associations (from GenCC):

• atrial septal defect 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• dilated cardiomyopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ENSG00000294801 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077653.2. 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
	TBX20	NM_001077653.2	MANE Select	c.1329G>A	p.Met443Ile	missense	Exon 8 of 8	NP_001071121.1	Q9UMR3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX20	ENST00000408931.4	TSL:1 MANE Select	c.1329G>A	p.Met443Ile	missense	Exon 8 of 8	ENSP00000386170.3	Q9UMR3
	ENSG00000294801	ENST00000726058.1		n.427C>T		non_coding_transcript_exon	Exon 2 of 2
	ENSG00000294801	ENST00000726056.1		n.166+429C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1386272 Hom.: 0 Cov.: 34 AF XY: 0.00000436 AC XY: 3 AN XY: 687970

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

African (AFR) AF: 0.00 AC: 0 AN: 31154

American (AMR) AF: 0.00 AC: 0 AN: 41132

Ashkenazi Jewish (ASJ) AF: 0.0000427 AC: 1 AN: 23420

East Asian (EAS) AF: 0.00 AC: 0 AN: 33806

South Asian (SAS) AF: 0.00 AC: 0 AN: 83556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 9.39e-7 AC: 1 AN: 1064996

Other (OTH) AF: 0.0000180 AC: 1 AN: 55636

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000625500), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.057	D
MutationAssessor	Benign	0.55	N
PhyloP100		7.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.34	N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.17	T
Polyphen		0.53	P
Vest4		0.87
MutPred		0.23		Gain of catalytic residue at P445 (P = 0.0307)
MVP		0.86
MPC		0.75
ClinPred		0.80	D
GERP RS		5.7
Varity_R		0.78
gMVP		0.50
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs1789317610; hg19: chr7-35242057;