rs375484585

chr7-35202464-C-Achr7-35202464-C-T

Variant summary

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

The NM_001077653.2(TBX20):c.1310G>T(p.Arg437Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 1,600,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R437C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: TBX20 NM_001077653.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.57

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 7-35202464-C-A is Benign according to our data. Variant chr7-35202464-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1604200.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX20	NM_001077653.2	c.1310G>T	p.Arg437Leu	missense_variant	8/8	ENST00000408931.4
TBX20	XM_017012456.2	c.713G>T	p.Arg238Leu	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX20	ENST00000408931.4	c.1310G>T	p.Arg437Leu	missense_variant	8/8	1	NM_001077653.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 149850 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000986 AC: 23 AN: 233228 Hom.: 0 AF XY: 0.000151 AC XY: 19 AN XY: 126120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000771

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000953

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000427 AC: 62 AN: 1450948 Hom.: 0 Cov.: 33 AF XY: 0.0000666 AC XY: 48 AN XY: 720794

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: 0.000710

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149954 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73032

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000828 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2020

The p.R437L variant (also known as c.1310G>T), located in coding exon 8 of the TBX20 gene, results from a G to T substitution at nucleotide position 1310. The arginine at codon 437 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.086	T
Polyphen		0.99	D
Vest4		0.84
MutPred		0.37		Gain of catalytic residue at S439 (P = 0.0594);
MVP		0.84
MPC		1.8
ClinPred		0.33	T
GERP RS		5.7
Varity_R		0.19
gMVP		0.65

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: rs375484585; hg19: chr7-35242076;