rs267607106

Variant names:

• chr7-35249968-G-C
• rs267607106
• NM_001077653.2:c.363C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001077653.2(TBX20):​c.363C>G​(p.Ile121Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I121N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX20 NM_001077653.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.97
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 7-35249968-G-C is Pathogenic according to our data. Variant chr7-35249968-G-C is described in CliVar as Pathogenic. Clinvar id is 4634.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-35249968-G-C is described in CliVar as Pathogenic. Clinvar id is 4634.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-35249968-G-C is described in CliVar as Pathogenic. Clinvar id is 4634.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX20	NM_001077653.2	c.363C>G	p.Ile121Met	missense_variant	Exon 2 of 8	ENST00000408931.4	NP_001071121.1
TBX20	NM_001166220.1	c.363C>G	p.Ile121Met	missense_variant	Exon 2 of 6		NP_001159692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX20	ENST00000408931.4	c.363C>G	p.Ile121Met	missense_variant	Exon 2 of 8	1	NM_001077653.2	ENSP00000386170.3
TBX20	ENST00000492961.1	n.374C>G		non_coding_transcript_exon_variant	Exon 2 of 6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atrial septal defect 4 Pathogenic:1

Apr 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		5.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Gain of disorder (P = 0.0421);
MVP		0.93
MPC		1.6
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.88
gMVP		0.69
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267607106; hg19: chr7-35289580;