rs201217462

chr7-35202443-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001077653.2(TBX20):c.1331C>T(p.Thr444Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,559,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T444T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TBX20 NM_001077653.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 7-35202443-G-A is Benign according to our data. Variant chr7-35202443-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 519187.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX20	NM_001077653.2	c.1331C>T	p.Thr444Met	missense_variant	8/8	ENST00000408931.4
TBX20	XM_017012456.2	c.734C>T	p.Thr245Met	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX20	ENST00000408931.4	c.1331C>T	p.Thr444Met	missense_variant	8/8	1	NM_001077653.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000865 AC: 13 AN: 150352 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000591

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000109 AC: 25 AN: 229982 Hom.: 0 AF XY: 0.0000886 AC XY: 11 AN XY: 124166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000919

Gnomad ASJ exome AF: 0.00124

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000872

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000121 AC: 171 AN: 1409292 Hom.: 0 Cov.: 34 AF XY: 0.000109 AC XY: 76 AN XY: 698988

Gnomad4 AFR exome AF: 0.0000628

Gnomad4 AMR exome AF: 0.000120

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000239

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.000245

GnomAD4 genome AF: 0.0000864 AC: 13 AN: 150474 Hom.: 0 Cov.: 31 AF XY: 0.0000817 AC XY: 6 AN XY: 73434

Gnomad4 AFR AF: 0.0000976

Gnomad4 AMR AF: 0.0000663

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000591

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000745 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2021	Reported as a single nucleotide polymorphism (SNP) in an individual with an atrial septal defect (Monroy-Munoz et al., 2015); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 519187; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25834824) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 07, 2023	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.87
MPC		1.5
ClinPred		0.23	T
GERP RS		5.7
Varity_R		0.26
gMVP		0.46

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: rs201217462; hg19: chr7-35242055; COSMIC: COSV101282449;